Pyrimidine derivatives as kinase inhibitors

ABSTRACT

The invention provides novel pyrimidine derivatives of formula (I) and pharmaceutical compositions thereof, and methods for using such compounds. For example, the pyrimidine derivatives of the invention may be used to treat, ameliorate or prevent a condition which responds to inhibition of insulin-like growth factor (IGF-IR) or analplastic lymphoma kinase (ALK).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application Ser.No. 61/075,583, filed 25 Jun. 2008, which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

The invention relates to protein kinase inhibitors, more particularlynovel pyrimidine derivatives and pharmaceutical compositions thereof,and their use as pharmaceuticals.

BACKGROUND ART

Insulin-like growth factor (IGF-1) signaling is highly implicated incancer, with the IGF-1 receptor (IGF-1R) as the predominating factor.IGR-1R is important for tumor transformation and survival of malignantcells, but is only partially involved in normal cell growth. Targetingof IGF-1R has been suggested to be a promising option for cancertherapy. (Larsson et al., Br. J. Cancer 92:2097-2101 (2005)).

Anaplastic lymphoma kinase (ALK), a member of the insulin receptorsuperfamily of receptor tyrosine kinases, has been implicated inoncogenesis in hematopoietic and non-hematopoietic tumors. The aberrantexpression of full-length ALK receptor proteins has been reported inneuroblastomas and glioblastomas; and ALK fusion proteins have occurredin anaplastic large cell lymphoma. The study of ALK fusion proteins hasalso raised the possibility of new therapeutic treatments for patientswith ALK-positive malignancies. (Pulford et al., Cell. Mol. Life. Sci.61:2939-2953 (2004)).

Because of the emerging disease-related roles of IGF-1R and ALK, thereis a continuing need for compounds which may be useful for treating andpreventing a disease which responds to inhibition of IGF-1R and ALK.

DISCLOSURE OF THE INVENTION

The invention relates to novel pyrimidine derivatives and pharmaceuticalcompositions thereof, and their use as pharmaceuticals.

In one aspect, the invention provides a compound of Formula (1):

or a physiologically acceptable salt thereof;

wherein W is

or W′;

W′ is pyridyl, isoquinolinyl, quinoliny, naphthalenyl, cinnolin-5-yl or[3-(C₁₋₆ alkyl)-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7yl], each ofwhich is optionally substituted with 1-3 R⁹; and said pyridyl,isoquinolinyl, quinolinyl and napthalenyl are each substituted on a ringcarbon with

X is —C(R)═N—O—R⁷, C(O)NRR⁷, C(O)NR—(CR₂)_(n)—NRR⁷, —(CR₂)_(p)NRRwherein two R groups together with N in NRR form a 5-6 membered ringcontaining 1-3 heteroatoms selected from N, O and S and optionallysubstituted with 1-3 R⁹, or a C₅₋₇ carbocycle optionally substitutedwith oxo, ═N—OH or R⁹; or X is quinolinyl,(1,2,3,4-tetrahydroisoquinolin-6-yl) or a 5-6 membered heteroaryl having1-3 heteroatoms selected from N, O and S, each of which is optionallysubstituted with 1-3 R⁹;

R¹ is halo, C₁₋₆ alkyl, or a halo-substituted C₁₋₆ alkyl;

R² is a 5-6 membered heteroaryl having 1-3 heteroatoms selected from N,O and S, and is optionally substituted with C₁₋₆ alkyl, C₁₋₆ haloalkylor C₃₋₇ cycloalkyl;

each R³ is H;

R⁴ is halo, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-substituted C₁₋₆alkyl, halo-substituted C₁₋₆ alkoxy, cyano or C(O)O₀₋₁R⁸;

R⁵ is H or

R⁶ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which may beoptionally substituted with halo and/or hydroxyl groups; —(CR₂)_(p)—OR⁷,—(CR₂)_(p) ^(—CH(OH)C) _(t)F_(2t+1) wherein t is 1-3, (CR₂)_(p)—CN;(CR₂)_(p)—NR(R⁷), —(CR₂)_(p)—C(O)OR⁷, (CR₂)_(p)NR(CR₂)_(p)OR⁷,

(CR₂)_(p)NR-L-C(O)R⁸, C(O)(CR₂)_(q)OR⁸, —C(O)O—(CR₂)_(p)—NRR⁷,—C(O)—(CR₂)_(p)—OR⁷, L-Y,

-L-C(O)R⁷, -L-C(O)—NRR⁷, -L-C(O)—NR—(CR₂)_(p)—NRR⁷,-L-C(O)NR(CR₂)_(p)OR⁷,

-L-C(O)—(CR₂)_(q)—NR—C(O)—R⁸, -L-C(O)NR(CR₂)_(p)SR⁷,-L-C(O)NR(CR₂)_(p)S(O)₁₋₂R⁸,

-L-S(O)₂R⁸, -L-S(O)₂—(CR₂)_(q)—NRR⁷, -L-S(O)₂NR(CR₂)_(p)NR(R⁷) or

-L-S(O)₂NR(CR₂)_(p)OR⁷;

alternatively, R⁶ is a radical selected from formula (a), (b), (c) or(d):

R¹⁰ is O, S, NR¹⁷, wherein R¹⁷ is H, C₁₋₆ alkyl, SO₂R^(8a) or CO₂R^(8a);

R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently selected from H; C₁₋₆alkoxy; C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which may beoptionally substituted with halo, amino or hydroxyl groups; or R¹¹ andR¹², R¹² and R¹⁵, R¹⁵ and R¹⁶, R¹³ and R¹⁴, or R¹³ and R¹⁵ together withthe atoms to which they are attached may form a 3-7 membered saturated,unsaturated or partially unsaturated ring containing 1-3 heteroatomsselected from N, O and S, and optionally substituted with oxo and 1-3 R⁹groups;

L is (CR₂)₁₋₄ or a bond;

Y is C₃₋₇ carbocyclic ring, C₆₋₁₀ aryl, or a 5-10 membered heteroaryl or4-10 membered heterocyclic ring, each of which is optionally substitutedwith 1-3 R⁹ groups;

R⁷, R⁸ and R^(8a) are independently C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl, each of which may be optionally substituted with halo,NRR^(7a), hydroxyl or cyano; (CR₂)_(q)Y or C₁₋₆ alkoxy; or R⁷ is H;

R⁹ is R⁴, C(O)NRR⁷ or NRR⁷;

R and R^(7a) are independently H or C₁₋₆ alkyl;

R and R⁷ together with N in each NRR⁷, and R and R^(7a) together with Nin NRR^(7a) may form a 5-6 membered ring containing 1-3 heteroatomsselected from N, O and S, and optionally substituted with oxo and 1-3 R⁴groups;

m is 2-4;

n and p are independently 1-4; and

q is 0-4.

In the above Formula (1), R² may be pyrazolyl or isoxazolyl, each ofwhich is substituted with C₁₋₆ alkyl or C₃₋₇ cycloalkyl.

In one embodiment, the invention provides a compound of Formula (2):

wherein W is W′;

W′ is pyridyl optionally substituted with C₁₋₆ alkyl, isoquinolinyl,quinolinyl, naphthalenyl, cinnolin-5-yl optionally substituted with C₁₋₆alkyl or [3-(C₁₋₆ alkyl)-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7yl]; andsaid pyridyl, isoquinolinyl, quinolinyl and napthalenyl are eachsubstituted on a ring carbon with

R⁶ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which may beoptionally substituted with halo, amino, hydroxyl or alkoxy;—(CR₂)_(p)—CH(OH)C_(t)F_(2t+1) wherein t is 1,

-L-C(O)—NRR⁷ or -L-S(O)₂R⁸;

L is (CR₂)₁₄;

R¹ and R⁷ are independently H or C₁₋₆ alkyl;

R⁸ is C₁₋₆ alkyl; and

R¹ and R³ are as defined in Formula (1).

In another embodiment, the invention provides a compound of Formula (3):

wherein Z is NH or O;

R⁴ is halo or C₁₋₆ alkyl;

R⁵ is H or

R⁶ is H; and

R¹ and R³ are as defined in Formula (1).

In yet another embodiment, the invention provides a compound of Formula(4):

wherein one of R^(4a), R^(4b) and R^(4c) is H and the others areindependently halo, C₁₋₆alkyl, C₁₋₆ alkoxy, halo-substituted C₁₋₆ alkylor halo-substituted C₁₋₆ alkoxy; and

X is as defined in Formula (1).

In the above Formula (4), X may be —C(R)═N—O—R⁷, C(O)NRR⁷,C(O)NR—(CR₂)_(n)—NRR⁷ or —(CR₂)_(p)NRR wherein two R groups togetherwith N in NRR form morpholinyl;

R⁷ is H or C₁₋₆ alkyl optionally substituted with hydroxyl or NRR^(7a);

each R is H or C₁₋₆ alkyl;

R and R⁷ together with N in each NRR⁷ and R and R^(7a) together with Nin NRR^(7a) may form a 5-6 membered ring containing 1-2 heteroatomsselected from N, O and S; and n and p are independently 1-4.Alternatively, X may be quinolinyl, (1,2,3,4-tetrahydroisoquinolin-6-yl)or a 5-6 membered heteroaryl selected from pyrazolyl, pyridyl,thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl or thiaxolyl, eachof which is optionally substituted with C₁₋₆ alkyl, hydroxyl, orC(O)NRR⁷; R⁷ is H or C₁₋₆ alkyl; and R is H or C₁₋₆ alkyl.

In another embodiment, the invention provides a compound of Formula (5):

wherein one of R^(4a), R^(4b) and R^(4c) is H and the others areindependently halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-substituted C₁₋₆ alkylor halo-substituted C₁₋₆ alkoxy;

Ring E is a C₆ carbocycle optionally substituted with oxo, ═N—OH or R⁹;

R⁹ is hydroxyl or NRR⁷;

R is H or C₁₋₆ alkyl;

R⁷ is C₁₋₆ alkyl or (CR₂)_(q)Y and Y is C₃ cycloalkyl;

alternatively, R and R⁷ together with N in NRR⁷ forms morpholinyl,piperidinyl, piperazinyl, (C₁₋₆ alkyl)-piperazinyl, or pyrrolidinyl,each of which is optionally substituted with hydroxyl; and

R¹ and R³ are as defined in Formula (1).

In the above Formula (4) and (5), R^(4b) may be H. In other examples,R^(4a) and R^(4c) are independently halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,halo-substituted C₁₋₆ alkyl or halo-substituted C₁₋₆ alkoxy.

In the above Formula (1)-(5), R¹ is chloro or a halo-substituted C₁₋₆alkyl. In other examples, R³ is H.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound having Formula (1), (2), (3), (4) or(5), and a physiologically acceptable excipient.

In yet another aspect, the invention provides methods for inhibitingIGF-1R in a cell, comprising contacting the cell with an effectiveamount of a compound having Formula (1), (2), (3), (4) or (5) or apharmaceutical composition thereof.

The invention also provides methods to treat, ameliorate or prevent acondition which responds to inhibition of IGF-1R or anaplastic lymphomakinase (ALK) in a mammal suffering from said condition, comprisingadministering to the mammal a therapeutically effective amount of acompound having Formula (1), (2), (3), (4) or (5) or a pharmaceuticalcomposition thereof, and optionally in combination with a secondtherapeutic agent. Alternatively, the present invention provides for theuse of a compound having Formula (1), (2), (3), (4) or (5), andoptionally in combination with a second therapeutic agent, in themanufacture of a medicament for treating a condition mediated by IGF-1Ror ALK. The compounds of the invention may be administered, for example,to a mammal suffering from an autoimmune disease, a transplantationdisease, an infectious disease or a cell proliferative disorder. Inparticular examples, the compounds of the invention may be used alone orin combination with a chemotherapeutic agent to treat a cellproliferative disorder, including but not limited to, multiple myeloma,neuroblastoma, synovial, hepatocellular, Ewing's Sarcoma or a solidtumor selected from a osteosarcoma, melanoma, and tumor of breast,renal, prostate, colorectal, thyroid, ovarian, pancreatic, lung, uterineor gastrointestinal tumor.

DEFINITIONS

“Alkyl” refers to a moiety and as a structural element of other groups,for example halo-substituted-alkyl and alkoxy, and may bestraight-chained or branched. An optionally substituted alkyl, alkenylor alkynyl as used herein may be optionally halogenated (e.g., CF₃), ormay have one or more carbons that is substituted or replaced with aheteroatom, such as NR, O or S (e.g., —OCH₂CH₂O—, alkylthiols,thioalkoxy, alkylamines, etc).

“Aryl” refers to a monocyclic or fused bicyclic aromatic ring containingcarbon atoms. “Arylene” means a divalent radical derived from an arylgroup. For example, an aryl group may be phenyl, indenyl, indanyl,naphthyl, or 1,2,3,4-tetrahydronaphthalenyl, which may be optionallysubstituted in the ortho, meta or para position.

“Heteroaryl” as used herein is as defined for aryl above, where one ormore of the ring members is a heteroatom. For example, a heteroarylsubstituent for use in the compounds of the invention may be amonocyclic or bicyclic 5-10 membered heteroaryl containing 1-4heteroatoms selected from N, O, and S. Examples of heteroaryls includebut are not limited to pyridyl, pyrazinyl, indolyl, indazolyl,quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl,benzo[1,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl,oxazolyl, isoxazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyrazolyl,thienyl, pyrrolyl, isoquinolinyl, purinyl, thiazolyl, tetrazinyl,benzothiazolyl, oxadiazolyl, benzoxadiazolyl, etc.

A “carbocyclic ring” as used herein refers to a saturated or partiallyunsaturated, monocyclic, fused bicyclic or bridged polycyclic ringcontaining carbon atoms, which may optionally be substituted, forexample, with ═O. Examples of carbocyclic rings include but are notlimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylene, cyclohexanone, etc.

A “heterocyclic ring” as used herein is as defined for a carbocyclicring above, wherein one or more ring carbons is a heteroatom. Forexample, a heterocyclic ring for use in the compounds of the inventionmay be a 4-7 membered heterocyclic ring containing 1-3 heteroatomsselected from N, O and S, or a combination thereof such as —S(O) or—S(O)₂—. Examples of heterocyclic rings include but are not limited toazetidinyl, morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl,piperidinyl, piperidinylone, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl,1,2,3,4-tetrahydroquinolinyl, etc. Heterocyclic rings as used herein mayencompass bicyclic amines and bicyclic diamines.

As used herein, an H atom in any substituent groups (e.g., CH₂)encompasses all suitable isotopic variations, e.g., H, ²H and ³H.

The term “pharmaceutical combination” as used herein refers to a productobtained from mixing or combining active ingredients, and includes bothfixed and non-fixed combinations of the active ingredients. The term“fixed combination” means that the active ingredients, e.g. a compoundof Formula (1) and a co-agent, are both administered to a patientsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that the active ingredients, e.g. acompound of Formula (1) and a co-agent, are both administered to apatient as separate entities either simultaneously, concurrently orsequentially with no specific time limits, wherein such administrationprovides therapeutically effective levels of the active ingredients inthe body of the patient. The latter also applies to cocktail therapy,e.g. the administration of three or more active ingredients.

“Mammal” refers to any animal classified as a mammal, including humans,domestic and farm animals, and zoo, sports, or pet animals, such asdogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. Inparticular examples, the mammal is human.

The term “administration” or “administering” of the subject compoundmeans providing a compound of the invention and prodrugs thereof to asubject in need of treatment. Administration “in combination with” oneor more further therapeutic agents includes simultaneous (concurrent)and consecutive administration in any order, and in any route ofadministration.

An “effective amount” of a compound is an amount sufficient to carry outa specifically stated purpose. An “effective amount” may be determinedempirically and in a routine manner, in relation to the stated purpose.

The term “therapeutically effective amount” refers to an amount of acompound (e.g., an IGF-1R antagonist) effective to “treat” anIGF-1R-mediated disorder in a subject or mammal. In the case of cancer,the therapeutically effective amount of the drug may reduce the numberof cancer cells; reduce the tumor size; inhibit (i.e., slow to someextent and preferably stop) cancer cell infiltration into peripheralorgans; inhibit (i.e., slow to some extent and preferably stop) tumormetastasis; inhibit, to some extent, tumor growth; and/or relieve tosome extent one or more of the symptoms associated with the cancer. Seethe definition herein of “treating”. To the extent the drug may preventgrowth and/or kill existing cancer cells, it may be cytostatic and/orcytotoxic.

The term “cancer” refers to the physiological condition in mammals thatis typically characterized by unregulated cell growth/proliferation.Examples of cancer include, but are not limited to: carcinoma, lymphoma,blastoma, and leukemia. More particular examples of cancers include, butare not limited to: chronic lymphocytic leukemia (CLL), lung, includingnon small cell (NSCLC), breast, ovarian, cervical, endometrial,prostate, colorectal, intestinal carcinoid, bladder, gastric,pancreatic, hepatic (hepatocellular), hepatoblastoma, esophageal,pulmonary adenocarcinoma, mesothelioma, synovial sarcoma, osteosarcoma,head and neck squamous cell carcinoma, juvenile nasopharyngealangiofibromas, liposarcoma, thyroid, melanoma, basal cell carcinoma(BCC), medulloblastoma and desmoid.

“Treating” or “treatment” or “alleviation” refers to both therapeutictreatment and prophylactic or preventative measures, wherein the objectis to prevent or slow down (lessen) the targeted pathologic disease orcondition or disorder. Those in need of treatment include those alreadywith the disorder as well as those prone to having the disorder or thosein whom the disorder is to be prevented (prophylaxis). When theIGF-1R-mediated disorder is cancer, a subject or mammal is successfully“treated” or shows a reduced tumor burden if, after receiving atherapeutic amount of an IGF-1R antagonist according to the methods ofthe present invention, the patient shows observable and/or measurablereduction in or absence of one or more of the following: reduction inthe number of cancer cells or absence of the cancer cells; reduction inthe tumor size; inhibition (i.e., slow to some extent and preferablystop) of cancer cell infiltration into peripheral organs including thespread of cancer into soft tissue and bone; inhibition (i.e., slow tosome extent and preferably stop) of tumor metastasis; inhibition, tosome extent, of tumor growth; and/or relief to some extent, one or moreof the symptoms associated with the specific cancer; reduced morbidityand mortality, and improvement in quality of life issues. To the extentthe IGF-1R antagonist may prevent growth and/or kill existing cancercells, it may be cytostatic and/or cytotoxic. Reduction of these signsor symptoms may also be felt by the patient.

“Carriers” as used herein include pharmaceutically acceptable carriers,excipients, or stabilizers which are nontoxic to the cell or mammalbeing exposed thereto at the dosages and concentrations employed. Oftenthe physiologically acceptable carrier is an aqueous pH bufferedsolution. Examples of physiologically acceptable carriers includebuffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid; low molecular weight (less thanabout 10 residues) polypeptide; proteins, such as serum albumin,gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides, andother carbohydrates including glucose, mannose, or dextrins; chelatingagents such as EDTA; sugar alcohols such as mannitol or sorbitol;salt-forming counterions such as sodium; and/or nonionic surfactantssuch as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer. Examples of chemotherapeutic agents includealkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines suchas benzodopa, carboquone, meturedopa, and uredopa; ethylenimines andmethylamelamines including altretamine, triethylenemelamine,trietylenephosphoramide, triethiylenethiophosphoramide andtrimethylolomelamine; acetogenins (especially bullatacin andbullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®);beta-lapachone; lapachol; colchicines; betulinic acid; a camptothecin(including the synthetic analogue topotecan (HYCAMTIN®), CPT-11(irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including itsadozelesin, carzelesin and bizelesin synthetic analogues);podophyllotoxin; podophyllinic acid; teniposide; cryptophycins(particularly cryptophycin 1 and cryptophycin 8); dolastatin;duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1);eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine;antibiotics such as the enediyne antibiotics (e.g., calicheamicin,especially calicheamicin gamma1I and calicheamicin omegaI1 (see, e.g.,Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994)); dynemicin, includingdynemicin A; an esperamicin; as well as neocarzinostatin chromophore andrelated chromoprotein enediyne antibiotic chromophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN®doxorubicin (including morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin,mitomycins such as mitomycin C, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS NaturalProducts, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium;tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine;trichothecenes (especially T-2 toxin, verracurin A, roridin A andanguidine); urethan; vindesine (ELDISINE®, FILDESIN®); dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); thiotepa; taxoids, e.g., TAXOL® paclitaxel(Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™Cremophor-free, albumin-engineered nanoparticle formulation ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil;gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine(VELBAN®); platinum; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine (ONCOVIN®); oxaliplatin; leucovovin; vinorelbine(NAVELBINE®); novantrone; edatrexate; daunomycin; aminopterin;ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine(DMFO); retinoids such as retinoic acid; capecitabine (XELODA®);pharmaceutically acceptable salts, acids or derivatives of any of theabove; as well as combinations of two or more of the above such as CHOP,an abbreviation for a combined therapy of cyclophosphamide, doxorubicin,vincristine, and prednisolone, and FOLFOX, an abbreviation for atreatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU andleucovovin.

Furthermore, a “chemotherapeutic agent” may include anti-hormonal agentsthat act to regulate, reduce, block, or inhibit the effects of hormonesthat can promote the growth of cancer, and are often in the form ofsystemic, or whole-body treatment. They may be hormones themselves.Examples include anti-estrogens and selective estrogen receptormodulators (SERMs), including, for example, tamoxifen (includingNOLVADEX® tamoxifen), EVISTA® raloxifene, droloxifene,4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, andFARESTON® toremifene; anti-progesterones; estrogen receptordown-regulators (ERDs); agents that function to suppress or shut downthe ovaries, for example, leutinizing hormone-releasing hormone (LHRH)agonists such as LUPRON® and ELIGARD® leuprolide acetate, goserelinacetate, buserelin acetate and tripterelin; other anti-androgens such asflutamide, nilutamide and bicalutamide; and aromatase inhibitors thatinhibit the enzyme aromatase, which regulates estrogen production in theadrenal glands, such as, for example, 4(5)-imidazoles,aminoglutethimide, MEGASE® megestrol acetate, AROMASIN® exemestane,formestanie, fadrozole, RIVISOR® vorozole, FEMARA® letrozole, andARIMIDEX® anastrozole. In addition, such definition of chemotherapeuticagents includes bisphosphonates such as clodronate (for example,BONEFOS® or OSTAC®), DIDROCAL® etidronate, NE-58095, ZOMETA® zoledronicacid/zoledronate, FOSAMAX® alendronate, AREDIA® pamidronate, SKELID®tiludronate, or ACTONEL® risedronate; as well as troxacitabine (a1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides,particularly those that inhibit expression of genes in signalingpathways implicated in abherant cell proliferation, such as, forexample, PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor(EGF-R); vaccines such as THERATOPE® vaccine and gene therapy vaccines,for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID®vaccine; LURTOTECAN® topoisomerase 1 inhibitor; ABARELIX® rmRH;lapatinib ditosylate (an ErbB-2 and EGFR dual tyrosine kinasesmall-molecule inhibitor also known as GW572016); and pharmaceuticallyacceptable salts, acids or derivatives of any of the above.

MODES OF CARRYING OUT THE INVENTION

The invention provides novel pyrimidine derivatives and pharmaceuticalcompositions thereof, and methods for using such compounds.

In one aspect, the invention provides a compound of Formula (1):

or a physiologically acceptable salt thereof;

wherein W is

or W′;

W′ is pyridyl, isoquinolinyl, quinoliny, naphthalenyl, cinnolin-5-yl or[3-(C₁₋₆ alkyl)-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7yl], each ofwhich is optionally substituted with 1-3 R⁹; and said pyridyl,isoquinolinyl, quinolinyl and napthalenyl are each substituted on a ringcarbon with

X is —C(R)═N—O—R⁷, C(O)NRR⁷, C(O)NR—(CR₂)_(n)—NRR⁷, —(CR₂)_(p)NRRwherein two R groups together with N in NRR form a 5-6 membered ringcontaining 1-3 heteroatoms selected from N, O and S and optionallysubstituted with 1-3 R⁹, or a C₅₋₇ carbocycle optionally substitutedwith oxo, ═N—OH or R⁹; or X is quinolinyl,(1,2,3,4-tetrahydroisoquinolin-6-yl) or a 5-6 membered heteroaryl having1-3 heteroatoms selected from N, O and S, each of which is optionallysubstituted with 1-3 R⁹;

R¹ is halo, C₁₋₆ alkyl, or a halo-substituted C₁₋₆ alkyl;

R² is a 5-6 membered heteroaryl having 1-3 heteroatoms selected from N,O and S, and is optionally substituted with C₁₋₆ alkyl, C₁₋₆ haloalkylor C₃₋₇ cycloalkyl;

each R³ is H;

R⁴ is halo, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-substituted C₁₋₆alkyl, halo-substituted C₁₋₆ alkoxy, cyano or C(O)O₀₋₁R⁸;

R⁵ is H or

R⁶ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which may beoptionally substituted with halo and/or hydroxyl groups; —(CR₂)_(p)—OR⁷,—(CR₂)_(p)—CH(OH)C_(t)F_(2t+1) wherein t is 1-3, (CR₂)_(p)—CN;(CR₂)_(p)—NR(R⁷), —(CR₂)_(p)—C(O)OR⁷, (CR₂)_(p)NR(CR₂)_(p)OR⁷,

(CR₂)_(p)NR-L-C(O)R⁸, C(O)(CR₂)_(q)OR⁸, —C(O)O—(CR₂)_(p)—NRR⁷, —C(O)—(CR₂)_(p)—OR⁷, L-Y,

-L-C(O)R⁷, -L-C(O)—NRR⁷, -L-C(O)—NR—(CR₂)_(p)—NRR⁷,-L-C(O)NR(CR₂)_(p)OR⁷,

-L-C(O)—(CR₂)_(q)—NR—C(O)—R⁸, -L-C(O)NR(CR₂)_(p)SR⁷,-L-C(O)NR(CR₂)_(p)S(O)₁₋₂R⁸,

-L-S(O)₂R⁸, -L-S(O)₂—(CR₂)_(q)—NRR⁷, -L-S(O)₂NR(CR₂)_(p)NR(R⁷) or

-L-S(O)₂NR(CR₂)_(p)OR⁷;

alternatively, R⁶ is a radical selected from formula (a), (b), (c) or(d):

R₁₀ is O, S, NR¹⁷ wherein R¹⁷ is H, C₁₋₆ alkyl, SO₂R^(8a) or CO₂R^(8a);

R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently selected from H; C₁₋₆alkoxy; C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which may beoptionally substituted with halo, amino or hydroxyl groups; or R¹¹ andR¹², R¹² and R¹⁵, R¹⁵ and R¹⁶, R¹³ and R¹⁴, or R¹³ and R¹⁵ together withthe atoms to which they are attached may form a 3-7 membered saturated,unsaturated or partially unsaturated ring containing 1-3 heteroatomsselected from N, O and S, and optionally substituted with oxo and 1-3 R⁹groups;

L is (CR₂)₁₋₄ or a bond;

Y is C₃₋₇ carbocyclic ring, C₆₋₁₀ aryl, or a 5-10 membered heteroaryl or4-10 membered heterocyclic ring, each of which is optionally substitutedwith 1-3 R⁹ groups;

R⁷, R⁸ and R^(8a) are independently C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl, each of which may be optionally substituted with halo,NRR^(7a), hydroxyl or cyano; (CR₂)_(q)Y or C₁₋₆ alkoxy; or R⁷ is H;

R⁹ is R⁴, C(O)NRR⁷ or NRR⁷;

R and R^(7a) are independently H or C₁₋₆ alkyl;

R and R⁷ together with N in each NRR⁷, and R and R^(7a) together with Nin NRR^(7a) may form a 5-6 membered ring containing 1-3 heteroatomsselected from N, O and S, and optionally substituted with oxo and 1-3 R⁴groups;

m is 2-4;

n and p are independently 1-4; and

q is 0-4.

In one embodiment, the invention provides a compound of Formula (2):

wherein W is W′;

W′ is pyridyl optionally substituted with C₁₋₆ alkyl, isoquinolinyl,quinolinyl, naphthalenyl, cinnolin-5-yl optionally substituted with C₁₋₆alkyl or [3-(C₁₋₆ alkyl)-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7yl]; andsaid pyridyl, isoquinolinyl, quinolinyl and napthalenyl are eachsubstituted on a ring carbon with

R⁶ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which may beoptionally substituted with halo, amino, hydroxyl or alkoxy;—(CR₂)_(p)—CH(OH)C_(t)F_(2t+1) wherein t is 1,

-L-C(O)—NRR⁷ or -L-S(O)₂R⁸;

L is (CR₂)₁₋₄;

R and R⁷ are independently H or C₁₋₆ alkyl;

R⁸ is C₁₋₆ alkyl; and

R¹ and R³ are as defined in Formula (1).

In another embodiment, the invention provides a compound of Formula (3):

wherein Z is NH or O;

R⁴ is halo or C₁₋₆ alkyl;

R⁵ is H or

R⁶ is H; and

R¹ and R³ are as defined in Formula (1).

In yet another embodiment, the invention provides a compound of Formula(4):

wherein one of R^(4a), R^(4b) and R^(4c) is H and the others areindependently halo, C₁₋6 alkyl, C₁₋₆ alkoxy, halo-substituted C₁₋₆ alkylor halo-substituted C₁₋₆ alkoxy; and

X is as defined in Formula (1).

In another embodiment, the invention provides a compound of Formula (5):

wherein one of R^(4a), R^(4b) and R^(4c) is H and the others areindependently halo, C₁₋6 alkyl, C₁₋₆ alkoxy, halo-substituted C₁₋₆ alkylor halo-substituted C₁₋₆ alkoxy;

Ring E is a C₆ carbocycle optionally substituted with oxo, ═N—OH or R⁹;

R⁹ is hydroxyl or NRR⁷;

R is H or C₁₋₆ alkyl;

R⁷ is C₁₋₆ alkyl or (CR₂)_(q)Y and Y is C₃ cycloalkyl;

alternatively, R and R⁷ together with N in NRR⁷ forms morpholinyl,piperidinyl, piperazinyl, (C₁₋₆ alkyl)-piperazinyl, or pyrrolidinyl,each of which is optionally substituted with hydroxyl; and

R¹ and R³ are as defined in Formula (1).

In each of the above formula, any asymmetric carbon atoms may be presentin the (R)-, (S)- or (R,S)-configuration. The compounds may thus bepresent as mixtures of isomers or as pure isomers, for example, as pureenantiomers or diastereomers. The invention further encompasses possibletautomers of the inventive compounds.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given herein,except that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively.

The invention includes various isotopically labeled compounds as definedherein, for example, those into which radioactive isotopes such as ³H,¹³C, and ¹⁴C, are present. Such isotopically labelled compounds areuseful in metabolic studies (with, for example, ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques,such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. In otherexamples, an ¹⁸F or labeled compound may be used for PET or SPECTstudies. Isotopic variations of the compounds have the potential tochange a compound's metabolic fate and/or create small changes inphysical properties such as hydrophobicity, and the like. Isotopicvariations also have the potential to enhance efficacy and safety,enhance bioavailability and half-life, alter protein binding, changebiodistribution, increase the proportion of active metabolites and/ordecrease the formation of reactive or toxic metabolites. Isotopicallylabeled compounds of this invention and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent.

In each of the above formula, each optionally substituted moiety may besubstituted with C₁₋₆ alkyl, C₂₋₆ alkenyl or C₃₋₆ alkynyl, each of whichmay be optionally halogenated or optionally having a carbon that may bereplaced or substituted with N, S, O, or a combination thereof (forexample, hydroxyl C₁-C₈alkyl, C₁-C₈alkoxy C₁-C₈alkyl); halo, amino,amidino, C₁₋₆ alkoxy; hydroxyl, methylenedioxy, carboxy; C₁₋₈alkylcarbonyl, C₁₋₈alkoxycarbonyl, carbamoyl, C₁₋₈ alkylcarbamoyl,sulfamoyl, cyano, oxo, nitro, or an optionally substituted carbocyclicring, heterocyclic ring, aryl or heteroaryl as previously described.

Pharmacology and Utility

The compounds of the invention and their pharmaceutically acceptablesalts exhibit valuable pharmacological properties when tested in vitroin cell-free kinase assays and in cellular assays, and are thereforeuseful as pharmaceuticals.

In one aspect, the compounds of the invention may inhibit insulin likegrowth-factor receptor 1 (IGF-1R), and may be useful in the treatment ofIGF-1 R mediated diseases. Examples of IGF-1R mediated diseases includebut are not limited to proliferative diseases, such as tumors, forexample breast, renal, prostate, colorectal, thyroid, ovarian, pancreas,neuronal, lung, uterine and gastro intestinal tumors, as well asosteosarcomas and melanomas. The efficacy of the compounds of theinvention as inhibitors of IGF-1R tyrosine kinase activity may bedemonstrated using a cellular capture ELISA. In this assay, the activityof the compounds of the invention against (IGF-1)-inducedautophosphorylation of the IGF-1R is determined.

In another aspect, the compounds of the invention may inhibit thetyrosine kinase activity of anaplastic lymphoma kinase (ALK) and thefusion protein of NPM-ALK. This protein tyrosine kinase results from agene fusion of nucleophosmin (NPM) and ALK, rendering the proteintyrosine kinase activity of ALK ligand independent. NPM-ALK plays a keyrole in signal transmission in a number of hematopoetic and other humancells leading to hematological and neoplastic diseases, for example inanaplastic large-cell lymphoma (ALCL) and non-Hodgkin's lymphomas (NHL),specifically in ALK+NHL or Alkomas, in inflammatory myofibroblastictumors (IMT) and neuroblastomas. (Duyster et al. 2001 Oncogene 20,5623-5637). In addition to NPM-ALK, other gene fusions have beenidentified in human hematological and neoplastic diseases; for example,TPM3-ALK (a fusion of nonmuscle tropomyosin with ALK).

The inhibition of ALK tyrosine kinase activity may be demonstrated usingknown methods, for example using the recombinant kinase domain of theALK in analogy to the VEGF-R kinase assay described in J. Wood et al.Cancer Res. 60, 2178-2189 (2000). In general, in vitro enzyme assaysusing GST-ALK protein tyrosine kinase are performed in 96-well plates asa filter binding assay in 20 mM Tris HCl, pH=7.5, 3 mM MgCl₂, 10 mMMnCl₂, 1 mM DTT, 0.1 μCi/assay (=30 μl) [γ-³³P]-ATP, 2 μM ATP, 3 μg/mLpoly (Glu, Tyr 4:1) Poly-EY (Sigma P-0275), 1% DMSO, 25 ng ALK enzyme.Assays are incubated for 10 min at ambient temperature. Reactions areterminated by adding 50 μl of 125 mM EDTA, and the reaction mixture istransferred onto a MAIP Multiscreen plate (Millipore, Bedford, Mass.,USA), previously wet with methanol, and rehydrated for 5 min with H₂O.Following washing (0.5% H₃PO₄), plates are counted in a liquidscintillation counter. IC₅₀ values are calculated by linear regressionanalysis of the percentage inhibition.

The compounds of the invention may potently inhibit the growth of humanNPM-ALK overexpressing murine BaF3 cells (DSMZ Deutsche Sammiung vonMikroorganismen and Zellkulturen GmbH, Germany). The expression ofNPM-ALK may be achieved by transfecting the BaF3 cell line with anexpression vector pClneo™ (Promega Corp., Madison Wis., USA) coding forNPM-ALK and subsequent selection of G418 resistant cells.Non-transfected BaF3 cells depend on IL-3 for cell survival. Incontrast, NPM-ALK expressing BaF3 cells (named BaF3-NPM-ALK hereinafter)can proliferate in the absence of IL-3 because they obtain proliferativesignal through NPM-ALK kinase. Putative inhibitors of the NPM-ALK kinasetherefore abolish the growth signal and may result in antiproliferativeactivity. The antiproliferative activity of putative inhibitors of theNPM-ALK kinase can however be overcome by addition of IL-3, whichprovides growth signals through an NPM-ALK independent mechanism. Ananalogous cell system using FLT3 kinase has also been described (see, EWeisberg et al. Cancer Cell; 1, 433-443 (2002)).

The inhibitory activity of the compounds of the invention may bedetermined as follows. In general, BaF3-NPM-ALK cells (15,000/microtitreplate well) are transferred to 96-well microtitre plates. Test compoundsdissolved in dimethyl sulfoxide (DMSO) are added in a series ofconcentrations (dilution series) in such a manner that the finalconcentration of DMSO is not greater than 1% (v/v). After the addition,the plates are incubated for two days during which the control cultureswithout test compound are able to undergo two cell-division cycles. Thegrowth of the BaF3-NPM-ALK cells is measured by means of YOPRO™ staining[T Idziorek et al. J. Immunol. Methods; 185: 249-258 (1995)]: 25 μl oflysis buffer comprising 20 mM sodium citrate, pH 4.0, 26.8 mM sodiumchloride, 0.4% NP40, 20 mM EDTA and 20 mM is added to each well. Celllysis is completed within 60 min at room temperature and total amount ofYOPRO™ bound to DNA is determined by measurement using the Cytofluor II96-well reader (PerSeptive Biosystems) with the following settings:Excitation (nm) 485/20 and Emission (nm) 530/25.

The compounds of the invention may also be useful in the treatmentand/or prevention of acute or chronic inflammatory diseases or disordersor autoimmune diseases e.g. rheumatoid arthritis, osteoarthritis,systemic lupus erythematosus, Hashimoto's thyroiditis, multiplesclerosis, myasthenia gravis, diabetes (type I and II) and the disordersassociated therewith, respiratory diseases such as asthma orinflammatory liver injury, inflammatory glomerular injury, cutaneousmanifestations of immunologically-mediated disorders or illnesses,inflammatory and hyperproliferative skin diseases (such as psoriasis,atopic dermatitis, allergic contact dermatitis, irritant contactdermatitis and further eczematous dermatitis, seborrhoeic dermatitis), sinflammatory eye diseases, e.g. Sjoegren's syndrome,keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn'sdisease or ulcerative colitis.

In accordance with the foregoing, the present invention provides:

(1) a compound of the invention for use as a pharmaceutical;

(2) a compound of the invention for use as an IGF-1R inhibitor, forexample for use in any of the particular indications hereinbefore setforth;

(3) a pharmaceutical composition, e.g. for use in any of the indicationsherein before set forth, comprising a compound of the invention asactive ingredient together with one or more pharmaceutically acceptablediluents or carriers;

(4) a method for the treatment of any particular indication set forthhereinbefore in a subject in need thereof which comprises administeringan effective amount of a compound of the invention or a pharmaceuticalcomposition comprising same;

(5) the use of a compound of the invention for the manufacture of amedicament for the treatment or prevention of a disease or condition inwhich IGF-1R activation plays a role or is implicated;

(6) the method as defined above under (4) comprising co-administration,e.g. concomitantly or in sequence, of a therapeutically effective amountof a compound of the invention and one or more further drug substances,said further drug substance being useful in any of the particularindications set forth hereinbefore;

(7) a combination comprising a therapeutically effective amount of acompound of the invention and one or more further drug substances, saidfurther drug substance being useful in any of the particular indicationsset forth hereinbefore;

(8) use of a compound of the invention for the manufacture of amedicament for the treatment or prevention of a disease which respondsto inhibition of the anaplastic lymphoma kinase;

(9) the use according to (8), wherein the disease to be treated isselected from anaplastic large cell lymphoma, non-Hodgkin's lymphomas,inflammatory myofibroblastic tumors, neuroblastomas and neoplasticdiseases;

(10) the use according to (8) or (9), wherein the compound is of Formula(1), (2), (3), (4) or (5), or any one of the examples, or apharmaceutically acceptable salt thereof;

(11) a method for the treatment of a disease which responds toinhibition of the anaplastic lymphoma kinase, especially a diseaseselected from anaplastic large-cell lymphoma, non Hodgkin's lymphomas,inflammatory myofibroblastic tumors, neuroblastomas and neoplasticdiseases, comprising administering an effective amount of a compound ofthe invention or a pharmaceutically acceptable salt thereof.

Administration and Pharmaceutical Compositions

In general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors known tothose of ordinary skill in the art. For example, for the treatment ofneoplastic diseases and immune system disorders, the required dosagewill also vary depending on the mode of administration, the particularcondition to be treated and the effect desired.

In general, satisfactory results are indicated to be obtainedsystemically at daily dosages of from about 0.01 to about 100 mg/kg perbody weight, or particularly, from about 0.03 to 2.5 mg/kg per bodyweight. An indicated daily dosage in the larger mammal, e.g. humans, maybe in the range from about 0.5 mg to about 2000 mg, or moreparticularly, from about 0.5 mg to about 100 mg, convenientlyadministered, for example, in divided doses up to four times a day or inretard form. Suitable unit dosage forms for oral administration comprisefrom ca. 1 to 50 mg active ingredient.

Compounds of the invention may be administered as pharmaceuticalcompositions by any conventional route; for example, enterally, e.g.,orally, e.g., in the form of tablets or capsules; parenterally, e.g., inthe form of injectable solutions or suspensions; or topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form.

Pharmaceutical compositions comprising a compound of the presentinvention in free form or in a pharmaceutically acceptable salt form inassociation with at least one pharmaceutically acceptable carrier ordiluent may be manufactured in a conventional manner by mixing,granulating, coating, dissolving or lyophilizing processes. For example,pharmaceutical compositions comprising a compound of the invention inassociation with at least one pharmaceutical acceptable carrier ordiluent may be manufactured in conventional manner by mixing with apharmaceutically acceptable carrier or diluent. Unit dosage forms fororal administration contain, for example, from about 0.1 mg to about 500mg of active substance.

In one embodiment, the pharmaceutical compositions are solutions of theactive ingredient, including suspensions or dispersions, such asisotonic aqueous solutions. In the case of lyophilized compositionscomprising the active ingredient alone or together with a carrier suchas mannitol, dispersions or suspensions can be made up before use. Thepharmaceutical compositions may be sterilized and/or contain adjuvants,such as preserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure and/or buffers.Suitable preservatives include but are not limited to antioxidants suchas ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.The solutions or suspensions may further comprise viscosity-increasingagents, including but not limited to, sodium carboxymethylcellulose,carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, orsolubilizers, e.g. Tween 80 (polyoxyethylene(20)sorbitan mono-oleate).

Suspensions in oil may comprise as the oil component the vegetable,synthetic, or semi-synthetic oils customary for injection purposes.Examples include liquid fatty acid esters that contain as the acidcomponent a long-chained fatty acid having from 8 to 22 carbon atoms, orin some embodiments, from 12 to 22 carbon atoms. Suitable liquid fattyacid esters include but are not limited to lauric acid, tridecylic acid,myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearicacid, arachidic acid, behenic acid or corresponding unsaturated acids,for example oleic acid, elaidic acid, erucic acid, brassidic acid andlinoleic acid, and if desired, may contain antioxidants, for examplevitamin E, 3-carotene or 3,5-di-tert-butyl-hydroxytoluene. The alcoholcomponent of these fatty acid esters may have six carbon atoms and maybe monovalent or polyvalent, for example a mono-, di- or trivalent,alcohol. Suitable alcohol components include but are not limited tomethanol, ethanol, propanol, butanol or pentanol or isomers thereof;glycol and glycerol.

Other suitable fatty acid esters include but are not limitedethyl-oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL® M2375, (polyoxyethylene glycerol), LABRAFIL® M 1944 CS (unsaturatedpolyglycolized glycerides prepared by alcoholysis of apricot kernel oiland comprising glycerides and polyethylene glycol ester), LABRASOL™(saturated polyglycolized glycerides prepared by alcoholysis of TCM andcomprising glycerides and polyethylene glycol ester; all available fromGaKefosse, France), and/or MIGLYOL® 812 (triglyceride of saturated fattyacids of chain length C₈ to C₁₂ from Hills AG, Germany), and vegetableoils such as cottonseed oil, almond oil, olive oil, castor oil, sesameoil, soybean oil, or groundnut oil.

Pharmaceutical compositions for oral administration may be obtained, forexample, by combining the active ingredient with one or more solidcarriers, and if desired, granulating a resulting mixture, andprocessing the mixture or granules by the inclusion of additionalexcipients, to form tablets or tablet cores.

Suitable carriers include but are not limited to fillers, such assugars, for example lactose, saccharose, mannitol or sorbitol, cellulosepreparations, and/or calcium phosphates, for example tricalciumphosphate or calcium hydrogen phosphate, and also binders, such asstarches, for example corn, wheat, rice or potato starch,methylcellulose, hydroxypropyl methylcellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired,disintegrators, such as the above-mentioned starches, carboxymethylstarch, crosslinked polyvinylpyrrolidone, alginic acid or a saltthereof, such as sodium alginate. Additional excipients include flowconditioners and lubricants, for example silicic acid, talc, stearicacid or salts thereof, such as magnesium or calcium stearate, and/orpolyethylene glycol, or derivatives thereof.

Tablet cores may be provided with suitable, optionally enteric, coatingsthrough the use of, inter alia, concentrated sugar solutions which maycomprise gum arable, talc, polyvinylpyrrolidone, polyethylene glycoland/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures, or, for the preparation of entericcoatings, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Dyes or pigments may be added to the tablets or tablet coatings, forexample for identification purposes or to indicate different doses ofactive ingredient.

Pharmaceutical compositions for oral administration may also includehard capsules comprising gelatin or soft-sealed capsules comprisinggelatin and a plasticizer, such as glycerol or sorbitol. The hardcapsules may contain the active ingredient in the form of granules, forexample in admixture with fillers, such as corn starch, binders, and/orglidants, such as talc or magnesium stearate, and optionallystabilizers. In soft capsules, the active ingredient may be dissolved orsuspended in suitable liquid excipients, such as fatty oils, paraffinoil or liquid polyethylene glycols or fatty acid esters of ethylene orpropylene glycol, to which stabilizers and detergents, for example ofthe polyoxyethylene sorbitan fatty acid ester type, may also be added.

Pharmaceutical compositions suitable for rectal administration are, forexample, suppositories comprising a combination of the active ingredientand a suppository base. Suitable suppository bases are, for example,natural or synthetic triglycerides, paraffin hydrocarbons, polyethyleneglycols or higher alkanols.

Pharmaceutical compositions suitable for parenteral administration maycomprise aqueous solutions of an active ingredient in water-solubleform, for example of a water-soluble salt, or aqueous injectionsuspensions that contain viscosity-increasing substances, for examplesodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired,stabilizers. The active ingredient, optionally together with excipients,can also be in the form of a lyophilizate and can be made into asolution before parenteral administration by the addition of suitablesolvents. Solutions such as are used, for example, for parenteraladministration can also be employed as infusion solutions. Themanufacture of injectable preparations is usually carried out understerile conditions, as is the filling, for example, into ampoules orvials, and the sealing of the containers.

The compounds of the invention may be administered as the sole activeingredient, or together with other drugs useful against neoplasticdiseases or useful in immunomodulating regimens. For example, thecompounds of the invention may be used in accordance with the inventionin combination with pharmaceutical compositions effective in variousdiseases as described above, e.g. with cyclophosphamide, 5-fluorouracil,fludarabine, gemcitabine, cisplatinum, carboplatin, vincristine,vinblastine, etoposide, irinotecan, paclitaxel, docetaxel, rituxan,doxorubicine, gefitinib, or imatinib; or also with cyclosporins,rapamycins, ascomycins or their immunosuppressive analogs, e.g.cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus,corticosteroids, e.g. prednisone, cyclophosphamide, azathioprene,methotrexate, gold salts, sulfasalazine, antimalarials, brequinar,leflunomide, mizoribine, mycophenolic acid, mycophenolate, mofetil,15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g.monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4,CD7, CD25, CD28, I CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154,ICOS, LFA-1, VLA-4 or their ligands, or other immunomodulatorycompounds, e.g. CTLA41g.

The invention also provides for a pharmaceutical combinations, e.g. akit, comprising a) a first agent which is a compound of the invention asdisclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

Processes for Making Compounds of the Invention

General procedures for preparing compounds of the invention aredescribed in the Examples, infra. In the reactions described, reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, may be protectedto avoid their unwanted participation in the reactions. Conventionalprotecting groups may be used in accordance with standard practice (seee.g., T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry”, John Wiley and Sons, 1991).

The compounds of the invention, including their salts, are alsoobtainable in the form of hydrates, or their crystals may include forexample the solvent used for crystallization (present as solvates).Salts can usually be converted to compounds in free form, e.g., bytreating with suitable basic agents, for example with alkali metalcarbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, such as potassium carbonate or sodium hydroxide. A compoundof the invention in a base addition salt form may be converted to thecorresponding free acid by treating with a suitable acid (e.g.,hydrochloric acid, etc.). In view of the close relationship between thenovel compounds in free form and those in the form of their salts,including those salts that may be used as intermediates, for example inthe purification or identification of the novel compounds, any referenceto the free compounds is to be understood as referring also to thecorresponding salts, as appropriate.

Salts of the inventive compounds with a salt-forming group may beprepared in a manner known per se. Acid addition salts of compounds ofFormula (1), (2A), (2B), (3A) and (3B), may thus be obtained bytreatment with an acid or with a suitable anion exchange reagent.Pharmaceutically acceptable salts of the compounds of the invention maybe formed, for example, as acid addition salts, with organic orinorganic acids, from compounds of Formula (1), (2A), (2B), (3A) and(3B), with a basic nitrogen atom.

Suitable inorganic acids include, but are not limited to, halogen acids,such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitableorganic acids include, but are not limited to, carboxylic, phosphoric,sulfonic or sulfamic acids, for example acetic acid, propionic acid,octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lacticacid, fumaric acid, succinic acid, adipic acid, pimelic acid, subericacid, azelaic acid, -malic acid, tartaric acid, citric acid, aminoacids, such as glutamic acid or aspartic acid, maleic acid,hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid,adamantanecarboxylic acid, benzoic acid, salicylic acid, 4aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid,cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonicacid, ethane-1,2-disulfonic acid, benzenesulfonic acid,2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid,dodecylsulfuric acid, N cyclohexylsulfamic acid, N-methyl-, N-ethyl- orN-propyl-sulfamic acid, or other organic protonic acids, such asascorbic acid. For isolation or purification purposes, it is alsopossible to use pharmaceutically unacceptable salts, for examplepicrates or perchlorates. For therapeutic use, only pharmaceuticallyacceptable salts or free compounds are employed (where applicable in theform of pharmaceutical preparations).

Compounds of the invention in unoxidized form may be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention may be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs may beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention may be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal may be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc.,1999.

Compounds of the invention may be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. Resolution of enantiomers may be carried out usingcovalent diastereomeric derivatives of the compounds of the invention,or by using dissociable complexes (e.g., crystalline diastereomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and may bereadily separated by taking advantage of these dissimilarities. Thediastereomers may be separated by fractionated crystallization,chromatography, or by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture may be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John WileyAnd Sons, Inc., 1981.

In summary, the compounds of the invention may be made by a process asdescribed in the Examples; and

(a) optionally converting a compound of the invention into apharmaceutically acceptable salt;

(b) optionally converting a salt form of a compound of the invention toa non-salt form;

(c) optionally converting an unoxidized form of a compound of theinvention into a pharmaceutically acceptable N-oxide;

(d) optionally converting an N-oxide form of a compound of the inventionto its unoxidized form;

(e) optionally resolving an individual isomer of a compound of theinvention from a mixture of isomers;

(f) optionally converting a non-derivatized compound of the inventioninto a pharmaceutically acceptable prodrug derivative; and

(g) optionally converting a prodrug derivative of a compound of theinvention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used. The present invention is further exemplified, but not limited,by the following and Examples that illustrate the preparation of thecompounds of the invention.

Intermediate 12,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine

A mixture of 5-methyl-1H-pyrazol-3-amine (3.00 g, 30.9 mmol),2,4,5-trichloropyrimidine (5.67 g, 30.9 mmol, 1 equiv.) and Na₂CO₃ (3.60g, 34.0 mmol, 1.1 equiv.) in EtOH (100 mL) was heated at 40° C. for 24h. The solvent was removed in vacuo. The resulting residue waspartitioned between EtOAc (350 mL) and water (100 mL). The EtOAc layerwas washed with water (3×), saturated aqueous NaCl (1×) and dried overNa₂SO₄. The resulting EtOAc solution was concentrated in vacuo,providing the product2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine; ESMS m/z244.0 (M+H⁺).

Intermediate 22-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine

A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.06 g, 4.86mmol), 5-methyl-1H-pyrazol-3-amine (472.2 mg, 4.86 mmol) and sodiumcarbonate (2.06 g, 19.4 mmol) in 100 mL of EtOH was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuo.The crude solid was partitioned between EtOAc and water. The combinedorganic extracts were dried (Na₂SO₄), concentrated in vacuo, andpurified by silica chromatography (EtOAc/hexanes: 1/1) to afford2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine;ESMS m/z 278.0 (M+H⁺).

Intermediate 3 2,5-dimethyl-4-(3-methylisoxazol-5-yl)aniline

Step 1: 1-(2,5-dimethyl-4-nitrophenyl)ethanone

To a mixture of 1-Bromo-2,5-dimethyl-4-nitrobenzene (1 g, 4.34 mmol) andtributyl(1-ethoxyvinyl)tin (1.88 g, 5.2 mmol) in DMF (20 mL), was addedtetrakis(triphenylphospine) palladium (0) (250 mg, 5% mmol). Thereaction tube was sealed, the mixture was purged with N₂ for 3 min andthen heated at 90° C. under N₂ for overnight. The reaction was cooled toroom temperature and poured into aqueous HCl (1N, 100 mL). The mixturewas stirred for 1 hour, and then extracted with ethyl acetate (3×100mL). The organic extracts were combined, washed with brine andconcentrated. The crude product was purified with silica gelchromatography (20% ethyl acetate in hexanes) to afford1-(2,5-dimethyl-4-nitrophenyl)ethanone as a yellow solid.

Step 2: 1-(2,5-dimethyl-4-nitrophenyl)-3-(dimethylamino)but-2-en-1-one

A mixture of 1-(2,5-dimethyl-4-nitrophenyl)ethanone (Step 1, 300 mg,1.55 mmol) and 1,1-dimethoxy-N,N-dimethylethanamine (1 mL) was heated ina microwave at 130° C. for 10 min. The crude product was purified withsilica gel chromatography (60% ethyl acetate in hexanes) to afford1-(2,5-dimethyl-4-nitrophenyl)-3-(dimethylamino)but-2-en-1-one as ayellow solid.

Steps 3 and 4: 2,5-dimethyl-4-(3-methylisoxazol-5-yl)aniline

A mixture of1-(2,5-dimethyl-4-nitrophenyl)-3-(dimethylamino)but-2-en-1-one (Step 2,100 mg, 0.38 mmol) and hydroxylamine monohydrochloride (132 mg, 1.9mmol) in ethanol (3 mL) was heated in a microwave at 100° C. for 15 min.The obtained 5-(2,5-dimethyl-4-nitrophenyl)-3-methylisoxazole wasdissolved in methanol (10 mL). To this solution was added Pd/C (10%).The reaction mixture was degassed and purged with H₂ for several timesand stirred under H₂ (1 atm.) overnight. The mixture was filtered andconcentrated to afford 2,5-dimethyl-4-(3-methylisoxazol-5-yl)aniline.ESMS m/z 203 (M+H⁺).

Intermediate 4 2,5-dimethyl-4-(oxazol-5-yl)aniline

Step 1: To a mixture of 2,5-dimethyl-4-nitrobenzaldehyde (75 mg, 0.42mmol) and toluenesulfonylmethyl isocyanide (TOSMIC) (98 mg, 0.5 mmol) inmethanol (2 mL), was added sodium methoxide (68 mg, 1.26 mmol). Themixture was sealed and heated at 90° C. for 15 hr. The reaction mixturewas concentrated and partitioned between water and ethyl acetate. Theorganic layer was separated, dried over sodium sulfate and concentrated.The 5-(2,5-Dimethyl-4-nitrophenyl)oxazole obtained was used in the nextstep without purification.

Step 2: The 5-(2,5-dimethyl-4-nitrophenyl)oxazole obtained in the laststep was dissolved in methanol (10 mL). To the solution was added Pd/C(10%). The reaction mixture was degassed and purged with H₂ for severaltimes and then stirred under 1 atm. hydrogen gas overnight. The mixturewas filtered and concentrated to afford2,5-dimethyl-4-(oxazol-5-yl)aniline as a white solid. ESMS m/z 189(M+H⁺).

Intermediate 5 2,5-Dimethyl-4-(3-methyl-1H-pyrazol-5-yl)aniline

A mixture of1-(2,5-dimethyl-4-nitrophenyl)-3-(dimethylamino)but-2-en-1-one (100 mg,0.38 mmol) and hydrazine (60 uL, 1.9 mmol) in ethanol (3 mL) was heatedin a microwave at 100° C. for 15 min. The obtained5-(2,5-dimethyl-4-nitrophenyl)-3-methylpyrazol was dissolved in methanol(10 mL). To the solution was added Pd/C (10%). The reaction mixture wasdegassed and purged with H₂ for several times and stirred under 1 atm.hydrogen gas overnight. The mixture was filtered and concentrated toafford 2,5-Dimethyl-4-(3-methyl-1H-pyrazol-5-yl)aniline. ESMS m/z 202(M+H⁺).

Intermediate 6 2,5-Dimethyl-4-(2-methylthiazol-4-yl)aniline

Step 1: To a mixture of 1-(2,5-dimethyl-4-nitrophenyl)ethanone (300 mg,1.55 mmol) in HBr (48%) (5 mL)/methanol (2.4 mL) was added bromine (250mg, 1.55 mmol). The mixture was stirred at room temperature for 4 hrs.The mixture was diluted with water and extracted with ethyl acetate(2×20 mL). The organic layer was washed with brine and concentrated. Theresidue was purified with silica gel column chromatography (10% ethylacetate in hexanes) to afford2-bromo-1-(2,5-dimethyl-4-nitrophenyl)ethanone as a white solid.

Step 2: A mixture of 2-bromo-1-(2,5-dimethyl-4-nitrophenyl)ethanone (70mg, 0.26 mmol) and ethanethioamide (30 mg, 0.4 mmol) in ethanol (2 mL)was heated in a microwave at 150° C. for 20 min. The obtained4-(2,5-dimethyl-4-nitrophenyl)-2-methylthiazole was dissolved inmethanol (10 mL). To the solution was added Pd/C (10%). The reactionmixture was degassed and purged with H₂ for several times and stirredunder 1 atm. hydrogen gas overnight. The mixture was filtered andconcentrated to afford 2,5-dimethyl-4-(2-methylthiazol-4-yl)aniline.ESMS m/z 219 (M+H+).

Intermediate 7 2,5-Dimethyl-4-(1-methyl-1H-imidazol-2-yl)aniline

To a solution of 2-(2,5-dimethyl-4-nitrophenyl)-1H-imidazole (50 mg,0.23 mmol) in DMF (2 mL) was added NaH (11 mg, 0.46 mmol) at 0° C. Afterstirring for 15 min, iodomethane (65 mg, 0.46 mmol) was added dropwise.The mixture was stirred at 0° C. for 1 hr, and quenched by addingsaturated ammonium chloride aqueous solution. The mixture was extractedwith ethyl acetate (3×15 mL). The organic layer was washed with brineand dried over sodium sulfate. After concentration, the residue wasdissolved in methanol (10 mL). To the solution was added Pd/C (10%). Thereaction mixture was degassed and purged with H₂ for several times andstirred under 1 atm. hydrogen gas overnight. The mixture was filteredand concentrated to afford2,5-dimethyl-4-(1-methyl-1H-imidazol-2-yl)aniline. ESMS m/z 202 (M+H⁺).

Intermediate 8 2,5-dimethyl-4-(pyridin-3-yl)aniline

A suspension of 4-bromo-2,5-dimethylaniline (4.00 g, 20 mmol),pyridin-3-ylboronic acid (2.70 g, 11 mmol), Pd₂(dba)₃ (0.55 g, 0.6mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.98 g, 1.2mmol) and Na₂CO₃ (10.6 g, 100 mmol) in n-BuOH (50 mL) was degassed by astream of argon gas for 15 min. The reaction flask was sealed and placedin a pre-heated oil bath (115° C.). After stirring overnight, thereaction was cooled and filtered. The filter cake was washed with DCMand the filtrate was concentrated in vacuo. The resulting residue wasdissolved in EtOAc (150 mL). EtOAC is sequentially washed with water (20mL), brine (20 mL), dried over Na₂SO₄ and evaporated. The crude productwas purified by silica chromatography (0-50% EtOAC in hexanes gradient)to give 2,5-dimethyl-4-(pyridin-3-yl)aniline as a yellow solid; ESMS m/z199.1 (M+H⁺).

Intermediate 98-(2,5-dimethyl-4-nitrophenyl)-1,4-dixoaspiro[4.5]dec-7-ene

A mixture of4,4,4,4-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dixoaborolane(200 mg, 0.86 mmol), 1-bromo-2,5-dimethyl-4-nitrobenzene (228 mg, 0.86mmol), tetrakis(triphenylphosphine)palladium(0) (98 mg, 0.09 mmol), andcesium fluoride (392 mg, 2.58 mmol) in a mixture of 1,2-dimethoxyethane(2 mL) and methanol (1 mL) was degassed for 5 min, and then heated at130° C. in a microwave reactor for 15 min. The reaction was concentratedin vacuo, and purified by silica chromatography (EtOAC/hexanes:3/7) toafford 8-(2,5-dimethyl-4-nitrophenyl)-1,4-dixoaspiro[4.5]dec-7-ene; ESMSm/z 290.2 (M+H⁺).

Intermediate 10 2,5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline

A mixture of 8-(2,5-dimethyl-4-nitrophenyl)-1,4-dioxaspiro[4.5]decane(130.2 mg, 0.45 mmol) and 10% Pd—C (13.0 mg) in MeOH (20 mL) wasdegassed and then reacted under 1 atm. H₂. Upon reaction completion, thePd—C was removed by filtration and the filtrate was concentrated invacuo to afford 2,5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline;ESMS m/z 262.2 (M+H⁺).

Intermediate 112-fluoro-5-methyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline

A mixture of4,4,4,4-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane(532.0 mg, 2.0 mmol), 4-bromo-2-fluoro-5-methylaniline (406.0 mg, 2.0mmol), tetrakis(triphenylphosphine)palladium(0) (231.1 mg, 0.2 mmol),cesium fluoride (912.0 mg, 6.0 mmol), 1,2-dimethoxyethane (4 mL) andmethanol (2 mL) was degassed for 5 min and then heated at 130° C. in amicrowave reactor for 15 min. The reaction was concentrated in vacuo,and purified by silica chromatography (EtOAC/Hexanes:3/7) to afford2-fluoro-5-methyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline; ESMS m/z264.1 (M+H⁺).

Intermediate 122-fluoro-5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline

A mixture of2-fluoro-5-methyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline (130 mg,0.50 mmol) and 10% Pd—C (13.0 mg) in MeOH (20 mL) was degassed and thenreacted under 1 atm. H₂. Upon reaction completion, the Pd—C was removedby filtration and the filtrate was concentrated in vacuo to afford2-fluoro-5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline; ESMS m/z266.2 (M+H⁺).

Intermediate 134-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone

A mixture of 2-fluoro-5-methyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline(318.6 mg, 1.2 mmol),2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine(333.0 mg, 1.2 mmol) and HCl (4 N in water, 0.3 mL, 1.2 mmol) in i-PrOH(4.0 mL) was heated at 125° C. in an oil bath overnight. The reactionmixture was concentrated in vacuo. The resulting crude mixture wasdissolved in THF (4 mL), MeOH (2 mL) and HCl (4N in water, 0.3 mL, 1.2mmol), and stirred at room temperature for an additional 2 h. Thereaction mixture was concentrated in vacuo, and purified by silicachromatography (0-100% EtOAC in hexanes gradient) to afford4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone;ESMS m/z 463.2 (M+H⁺).

Intermediate 14 N-(2,5-dichloropyrimidin-4-yl)-5-methylisoxazol-3-amine

The mixture 5-methylisoxazol-3-amine (98 mg, 1.0 mmol),2,4,5-trichloropyrimidine (344 μL, 3.0 mmol), and sodium carbonate (106mg, 1.0 mmol) in 3 mL of EtOH was heated at 60° C. over night. Thereaction mixture was concentrated and then partitioned between EtOAc andbrine. The collected organic extracts were dried (Na₂SO₄), concentratedin vacuo, and purified with silica gel chromatography (MeOH/DCM: 1/9) toafford N-(2,5-dichloropyrimidin-4-yl)-5-methylisoxazol-3-amine; ESMS m/z245.0 (M+H⁺).

Intermediate 152,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine

A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (246 mg, 2.00 mmol),2,4,5-trichloropyrimidine (367 mg, 2.00 mmol, 1 equiv.) and Na₂CO₃ (233mg, 2.20 mmol, 1.1 equiv.) in EtOH (10 mL) was heated at 40° C. for 16h. The crude reaction mixture was diluted with EtOAc and sequentiallywashed with: water (3×) and saturated aqueous NaCl (1×). The resultingEtOAc layer was dried over Na₂SO₄ and then concentrated in vacuo,providing2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine; ESMSm/z 270.0 (M+H⁺).

Intermediate 16 tert-Butyl4-(6-amino-5-fluoro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate

Step 1: tert-Butyl4-(2-chloro-4-fluoro-5-nitrobenzamido)piperidine-1-carboxylate

Under N₂, to the solution of 2-chloro-4-fluoro-5-nitro-benzoic acid (1.0g, 4.56 mmol in 40 mL of DCM at 0° C. are added thionyl chloride (1.0mL, 13.68 mmol) and 0.1 mL of DMF sequentially. The reaction mixture waswarmed gradually to room temperature and stirred overnight. The reactionmixture was concentrated in vacuo to afford2-chloro-4-fluoro-5-nitrobenzoyl chloride. The crude was dissolved in 40mL of DCM, and 1-boc-4-aminopiperidine (910 mg, 4.56 mmol) andtriethylamine (1.29 mL, 9.12 mmol) were added to the solutionsequentially. After stirring at room temperature 1 h, the reactionmixture was washed with 20 mL of water. The organic extract was dried(Na₂SO₄), followed by concentration in vacuo to afford tert-Butyl4-(2-chloro-4-fluoro-5-nitrobenzamido)piperidine-1-carboxylate; ESMS m/z402.1 (M+H⁺).

Step 2: tert-Butyl4-(4-fluoro-5-nitro-2-vinylbenzamido)piperidine-1-carboxylate

Under nitrogen, the mixture of tert-butyl4-(2-chloro-4-fluoro-5-nitrobenzamido)piperidine-1-carboxylate (Step 1,1.52 g, 3.88 mmol), vinylboronic acid dibutyl ester (0.86 mL, 3.88mmol), dichlorobis(triphenylphosphine)palladium (II) (136 mg, 0.2 mmol)and sodium carbonate (2.9 g, 27.2 mmol) in THF (40 mL) and water (10 mL)was heated at 90° C. overnight. The reaction mixture was cooled to roomtemperature, partitioned between EtOAc and brine. The organic extractswere dried (Na₂SO₄), concentrated, and purified by silica gelchromatography (EtOAc/Hexanes:1/4) to afford tert-Butyl4-(4-fluoro-5-nitro-2-vinylbenzamido)piperidine-1-carboxylate; ESMS m/z394.2 (M+H⁺).

Step 3: tert-Butyl4-(5-fluoro-6-nitro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate

tert-Butyl 4-(4-fluoro-5-nitro-2-vinylbenzamido)piperidine-1-carboxylate(Step 2, 1.1 g, 2.77 mmol) in 50 mL of DCM is chilled to −78° C. Ozonewas passed through the solution until the starting material wasconsumed, and then nitrogen was passed through the solution for 5 min.The reaction mixture was warmed to room temperature.Triphenylphosphine-resin (2.77 g) in 10 mL of DCM was added, and wasstirred for another 1.5 h. The resin was filtered off, and the solutionwas concentrated in vacuo. The resulting crude was dissolved in DCM (15mL), and to this solution were added TFA (15 mL) and triethylsilane (1.0mL, 5.9 mmol) sequentially. The reaction was stirred at room temperature2 h. After concentration, the reaction crude was poured into 10 mL ofwater, neutralized to pH 8 with sat. aq. NaHCO₃, followed by addition of(Boc)₂O (603 mg, 2.77 mmol) in 10 mL of DCM. The reaction was stirred atroom temperature for 1.5 h, then extracted with DCM. The organicextracts were dried (Na₂SO₄), concentrated in vacuo, and purified bysilica gel chromatography (EtOAc/Hexanes:1/4) to give tert-Butyl4-(5-fluoro-6-nitro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate; ESMSm/z 380.2 (M+H⁺).

Step 4: tert-Butyl4-(6-amino-5-fluoro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate

The mixture of tert-butyl4-(5-fluoro-6-nitro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate (Step3, 240 mg, 0.72 mmol), Pd (10% wt on active carbon, 24 mg) and MeOH (20mL) was evacuated to remove air, and then the reaction was stirred undera hydrogen balloon until the starting material is consumed. Pd/C wasfiltered off and the solution was concentrated in vacuo to affordtert-Butyl4-(6-amino-5-fluoro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate; ESMSm/z 350.2 (M+H⁺).

Intermediate 17tert-butyl-4-(4-aminonaphthalen-1-yl)piperidine-1-carboxylate

Step 1:tert-butyl-4-(4-aminonaphthalen-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A mixture of 4-bromonaphthalen-1-amine (1.0 g, 4.5 mmol),tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(1.7 g, 5.4 mmol), Pd(PPh₃)₄ (26.01 mg, 0.02 mmol) and Na₂CO₃ (3.34 g,31.5 mmol) in 10 mL of DMF and 5 mL of water was degassed and purgedwith nitrogen. The reaction was heated at 100° C. for 5 h, and cooled toroom temperature. The reaction mixture was partitioned between EtOAc andwater. The combined organic extracts were dried (Na₂SO₄), concentratedin vacuo and purified by silica gel chromatography (MeOH/DCM: 5/95) toaffordtert-butyl-4-(4-aminonaphthalen-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate.

Step 2: tert-butyl-4-(4-aminonaphthalen-1-yl)piperidine-1-carboxylate

To a solution oftert-butyl-4-(4-aminonaphthalen-1-yl)-5,6-dihydropyridine-1(2H)-carboxylatein 50 mL of MeOH was added 10 wt % Pd—C (100 mg). The reaction wasdegassed to remove air and stirred under 1 atm. H₂ until the startingmaterial is consumed. The Pd—C was removed by filtration and theresulting solution was concentrated in vacuo to affordtert-butyl-4-(4-aminonaphthalen-1-yl)piperidine-1-carboxylate.

Intermediate 18 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine was synthesized bythe method described in the literature reference: Pecherer, B. et al. J.Heterocyclic Chem 1971, 8(5), 779-783, in conjunction with standardsynthetic methodology.

Example 11-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)ethanoneO-2-hydroxyethyloxime (28)

Step 1: To a solution ofN²-(4-bromo-2,5-dimethylphenyl)-5-chloro-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(280 mg, 0.69 mmol) in THF (3 mL) was added p-TSA (119 mg, 0.69 mmol)and 3,4-dihydro-2H-pyran (348 mg, 2.86 mmol). The mixture was stirred atroom temperature for 14 h and then poured into saturated aqueous NaHCO₃solution (10 mL). The resulting mixture was extracted with EtOAc (3×10mL) and the combined organic layers were concentrated. The resultingresidue was purified by flash column chromatography (silica gel, 0-50%EtOAc in hexanes gradient) to provideN²-(4-bromo-2,5-dimethylphenyl)-5-chloro-N⁴-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamineas a white solid; ESMS m/z 491.1 (M+H⁺).

Step 2: A mixture ofN²-(4-bromo-2,5-dimethylphenyl)-5-chloro-N⁴-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(166 mg, 0.34 mmol), tributyl(1-ethoxyvinyl)stannane (146 mg, 0.41 mmol)and Pd(PPh₃)₄ (39 mg, 0.034 mmol) in toluene (2 mL) was degassed andheated at 100° C. under N₂ for 14 h. After cooling down to roomtemperature, the mixture was concentrated. The resulting residue wasredissolved in acetonitrile (2 mL) and treated with 1N HCl (2 mL) for 14h. After extraction with EtOAc (3×15 mL), the combined organic layerswere treated with saturated aqueous KF (10 mL). The resulted organiclayer was collected and treated with brine and dried over MgSO₄. Afterremoving the drying agent by filtration, the filtrate was concentratedand purified by flash column chromatography (silica gel, 0-100% EtOAc inhexanes gradient) to provide1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)ethanoneas a white solid; ESMS m/z 371.1 (M+H⁺).

Step 3: To a solution of1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)ethanone(60 mg, 0.16 mmol) in MeOH (1 mL) was added AcOH (15 mg, 0.25 mmol),followed by the addition of 2-(aminooxy)ethanol (20 mg, 0.26 mmol). Themixture was heated to 60° C. for 14 h and cooled down to roomtemperature. The mixture was then purified directly by preparativeRP-HPLC to provide1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)ethanoneO-2-hydroxyethyl oxime; ESMS m/z 430.2 (M+H⁺).

Example 24-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-N-(2-(dimethylamino)ethyl)-2,5-dimethylbenzamide(31)

To a solution of4-(5-chloro-4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylbenzoicacid (35.0 mg, 0.077 mmol) in DMF (0.5 mL) was added HATU (29.1 mg,0.077 mmol), DIEA (26.7 μL, 0.153 mmol) andN¹,N¹-dimethylethane-1,2-diamine (25.2 μL, 0.230 mmol). The reactionmixture was stirred at room temperature overnight. 1N HCl aqueoussolution (0.5 mL) was then added and the reaction mixture was heated at100° C. for 1.5 hours to remove the tetrahydro-2H-pyran-2-yl protectinggroup. The mixture was purified by preparative RP-HPLC to provide4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-N-(2-(dimethylamino)ethyl)-2,5-dimethylbenzamide;ESMS m/z 443.2 (M+H⁺).

Example 34-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)cyclohexanoneoxime (33)

To a solution of4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)cyclohexanone(15 mg, 0.033 mmol) in MeOH (0.5 mL) was added NaOAc (6 mg, 0.073 mmol)and NH₂OH HCl (5 mg, 0.073 mmol). The resulting mixture was stirred at70° C. for 2 h. and then cooled down to room temperature. The mixturewas purified directly by preparative RP-HPLC to provide4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)-cyclohexanoneoxime; ESMS m/z 440.2 (M+H⁺).

Examples 4 and 55-chloro-N²-(2,5-dimethyl-4-(4-trans-morpholinocyclohexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(37)

5-chloro-N²-(2,5-dimethyl-4-(4-cis-morpholinocyclohexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(38)

Step 1: A mixture of 1-bromo-2,5-dimethyl-4-nitrobenzene (100 mg, 0.43mmol),4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane(112 mg, 0.43 mmol), Pd(PPh₃)₄ (49 mg, 0.043 mmol) and CsF (196 mg, 1.29mmol) in a mixture of dimethyl ethylene glycol and water (2:1, 1.5 mL)was degassed and heated under N₂ at 130° C. in microwave reactor for 15min. After cooling down to room temperature, the reaction mixture wastreated with saturated NH₄Cl aqueous solution (5 mL) and extracted withEtOAc (3×4 mL). The combined organic layers were concentrated andpurified by flash column chromatography (silica gel, 0%-30% EtOAc inhexanes gradient) to provide8-(2,5-dimethyl-4-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene as a whitesolid; ESMS m/z 290.1 (M+H⁺).

Step 2: A mixture of8-(2,5-Dimethyl-4-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (105 mg,0.36 mmol) and Pd/C (10 mg) in EtOH was degassed and stirred under 1atm. H₂ at room temperature for 14 h. Pd/C was removed by filtration andfiltrate was concentrated to provide2,5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline, which was used inthe next step without further purification; ESMS m/z 262.2 (M+H⁺).

Step 3: A mixture of2,5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline (86 mg, 0.33 mmol)and 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (104 mg,0.43 mmol) in ^(i)PrOH (3 mL) was treated with HCl (82 μL, 4N indioxane, 0.33 mmol) and heated to 125° C. in a sealed tube for 14 h.After cooling down to room temperature, the mixture was concentrated andwas treated with acetone (2 mL) and HCl (330 μL, 4N in dioxane) at roomtemperature for 5 h. The mixture was then treated with saturated NaHCO₃aqueous solution (10 mL) and extracted with EtOAc (3×10 mL). The organiclayers were combined, concentrated and purified by flash columnchromatography (silica gel, 0%-100% EtOAc in hexanes gradient) toprovide4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)cyclohexanoneas white solid; ESMS m/z 425.2 (M+H⁺).

Step 4: To a solution of4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)cyclohexanone(30 mg, 0.071 mmol) in 1,2-dichloroethane (1 mL) was added morpholine (9mg, 0.11 mmol) followed by AcOH (6.5 mg, 0.11 mmol) and 4 Å molecularsieves. The mixture was stirred at room temperature for 1 h before theaddition of sodium triacetoxyborohydride (22.5 mg, 0.11 mmol). Themixture was stirred at room temperature for 14 h at which pointadditional morpholine (5 mg, 0.058 mmol) and sodiumtriacetoxyborohydride (10 mg, 0.047 mmol) was added and stirred at roomtemperature for an additional 5 h. The reaction mixture was then treatedwith saturated NH₄Cl aqueous solution (3 mL) and extracted with EtOAc(3×4 mL). The combined organic layers were concentrated and purified bypreparative silica thin layer chromatography (7% MeOH/CH₂Cl₂ with 0.2%NH₃) to provide5-chloro-N²-(2,5-dimethyl-4-(4-cis-morpholinocyclo-hexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine_asthe less polar isomer; ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (br, 1H), 8.49(br, 2H), 7.98 (s, 1H), 7.10 (s, 1H), 7.00 (s, 1H), 6.13 (br, 1H), 3.64(m, 4H), 2.75 (m, 1H), 2.41 (m, 4H), 2.24 (s, 3H), 2.00-2.20 (m, 9H),1.70-1.85 (m, 2H), 1.35-1.55 (m, 4H); ESMS m/z 496.3 (M+H⁺) and5-chloro-N²-(2,5-dimethyl-4-(4-trans-morpholinocyclohexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine_asthe more polar isomer; ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (br, 1H), 8.47(br, 2H), 7.98 (s, 1H), 7.14 (s, 1H), 7.02 (s, 1H), 6.13 (br, 1H), 3.57(br, 4H), 2.60 (m, 1H), 2.50 (br, 4H), 2.32 (m, 1H), 2.22 (s, 3H), 2.13(s, 3H), 2.10 (s, 3H), 1.93 (b, 2H), 1.79 (b, 2H), 1.30-1.55 (m, 4H);ESMS m/z 496.3 (M+H⁺).

Example 65-Chloro-N²-(2,5-dimethyl-4-(morpholinomethyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(39)

Step 1: A mixture of2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (732 mg, 3mmol), 4-bromo-2,5-dimethylaniline (554 mg, 2 mmol) and conc. aqueousHCl (1.5 mL) in iso-propanol (15 mL) was heated in a microwave for 40min at 130° C. LCMS showed that the reaction was not complete, andadditional 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine(732 mg, 3 mmol) was added to the reaction. The reaction was againheated in a microwave for an additional 60 min at 130° C. The crudereaction mixture was then diluted with EtOAc (100 mL), sequentiallywashed with saturated aqueous NaHCO₃ (2×20 mL) and brine (10 mL), driedover Na₂CO₃ and concentrated in vacuo. The crude product was purified bysilica chromatography (0-10% MeOH in EtOAc gradient with 1% NH₃additive) to giveN²-(4-bromo-2,5-dimethylphenyl)-5-chloro-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamineas an off-white solid; ESMS m/z 407.2 (M+H⁺).

Step 2: A mixture ofN²-(4-bromo-2,5-dimethylphenyl)-5-chloro-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(41 mg, 0.1 mmol), potassium 1-trifluoroboratomethylmorpholine (43 mg,0.2 mmol), Pd(OAc)₂ (3 mg, 0.013 mmol), Xantphos (12 mg, 0.025 mmol) andCs₂CO₃ (98 mg, 0.3 mmol) in THF (1 mL)/H₂O (0.1 mL) was degassed by astream of argon gas. The vial was sealed and heated in a microwave for30 min at 160° C. Additional potassium 1-trifluoroboratomethylmorpholine(69 mg), Xantphos (18 mg) and Cs₂CO₃ (98 mg) were added. The reactionwas again heated in the microwave for an additional 30 min at 160° C.The crude product is purified by RP-HPLC to give5-Chloro-N2-(2,5-dimethyl-4-(morpholinomethyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamineas a white powder; ESMS m/z 428.2 (M+H⁺).

Example 74-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone(40)

A mixture of 2,5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline(111.3 mg, 0.43 mmol),2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine(119.6 mg, 0.43 mmol), HCl (4 N in water, 0.11 mL, 0.43 mmol) in i-PrOH(4.0 mL) was heated at 125° C. in an oil bath over night. The reactionmixture was concentrated in vacuo. The crude product was dissolved inTHF (2 mL), MeOH (1 mL) and HCl (4N in water, 0.11 mL, 0.43 mmol), andstirred at room temperature for 2 h. The reaction mixture wasconcentrated in vacuo, followed by purification by silica chromatography(0-100% EtOAc in hexanes gradient) to afford4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone;ESMS m/z 459.2 (M+H⁺).

Example 8trans-4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanol(41)

To a solution of4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone(100 mg, 0.22 mmol) in MeOH (15 mL) was added NaBH₄ (33.2 mg, 0.87mmol). The reaction was stirred 30 for min., concentrated and purifiedby silica chromatography (MeOH/DCM: 8:92) to affordtrans-4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanol;R_(f): 0.35 (silica; MeOH/DCM 8:92); ESMS m/z 461.2 (M+H⁺).

Example 9cis-4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanol(42)

To a solution of4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone(100 mg, 0.22 mmol) in MeOH (15 mL) was added NaBH₄ (33.2 mg, 0.87mmol). The reaction was stirred for 30 mins., concentrated and purifiedby silica chromatography (MeOH/DCM: 8:92) to affordcis-4-(2,5-dimethyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanol;R_(f): 0.45 (silica; MeOH/DCM 8:92); ESMS m/z 461.2 (M+H⁺).

Example 10N²-(2-fluoro-5-methyl-4-(cis-4-(piperidin-1-yl)cyclohexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine(62)

A mixture of4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone(30 mg, 0.065 mmol), piperidine (30 μL, 0.174 mmol) and acetic acid (75μL, 0.13 mmol) was stirred at room temperature for 1 h. Sodiumtriacetoxyborohydride (27.4 mg, 0.13 mmol) was added to the reaction andthe reaction mixture was stirred overnight. The mixture was concentratedand purified by silica chromatography (MeOH/DCM 8:92) to affordN²-(2-fluoro-5-methyl-4-(cis-4-(piperidin-1-yl)cyclohexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;R_(f): 0.41 (Silica; MeOH/DCM 8:92); ESMS m/z 532.3 (M+H⁺).

Example 11N²-(2-fluoro-5-methyl-4-(trans-4-(piperidin-1-yl)cyclohexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine(63)

A mixture of4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone(30 mg, 0.065 mmol), piperidine (30 μL, 0.174 mmol) and acetic acid (75μL, 0.13 mmol) was stirred at room temperature for 1 h. Sodiumtriacetoxyborohydride (27.4 mg, 0.13 mmol) was added to the reaction andthe reaction mixture was stirred overnight. The mixture was concentratedand purified by silica chromatography (MeOH/DCM 8:92) to affordN²-(2-fluoro-5-methyl-4-(trans-4-(piperidin-1-yl)cyclohexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;R_(f): 0.32 (Silica; MeOH/DCM 8:92); ESMS m/z 532.3 (M+H⁺).

Example 12N²-(2,5-dimethyl-4-(cis-4-morpholinocyclohexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine(66)

A mixture of4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone(40 mg, 0.087 mmol), morpholine (15 μL, 0.174 mmol) and acetic acid (75μL, 0.13 mmol) was stirred at room temperature for 1 h. Sodiumcyanoborohydride (8.2 mg, 0.13 mmol) was added to the reaction and thereaction mixture was stirred overnight. The mixture was concentrated andpurified by silica chromatography (MeOH/DCM 8:92) to affordN²-(2,5-dimethyl-4-(cis-4-morpholinocyclohexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;R_(f): 0.50 (Silica; MeOH/DCM 8:92); ESMS m/z 530.3 (M+H⁺).

Example 13N²-(2,5-dimethyl-4-(trans-4-morpholinocyclohexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine(67)

A mixture of4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone(40 mg, 0.087 mmol), morpholine (15 μL, 0.174 mmol) and acetic acid (75μL, 0.13 mmol) was stirred at room temperature for 1 h. Sodiumcyanoborohydride (8.2 mg, 0.13 mmol) was added to the reaction and thereaction mixture was stirred overnight. The mixture was concentrated andpurified by silica chromatography (MeOH/DCM 8:92) to affordN²-(2,5-dimethyl-4-(trans-4-morpholinocyclohexyl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine;R_(f): 0.38 (Silica; MeOH/DCM 8:92); ESMS m/z 530.3 (M+H⁺).

The following compounds in Table 1 are obtained by repeating theprocedures described in examples above and using appropriate startingmaterials.

TABLE 1 IGF1R Ba/F3 IC50 STRUCTURE NMR or ESMS (uM) 1

5-chloro-N2-(2-fluoro-5-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine ESMS m/z 413.1 (M + H+). 0.067 2

5-chloro-N2-(2-fluoro-5-methyl-4-(pyridin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMS m/z410.1 (M + H+). 0.103 3

5-chloro-N2-(2-fluoro-5-methyl-4-(pyridin-3-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMS m/z410.1 (M + H+). 0.067 4

5-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)-N-methylpicolinamide 1H NMR (400 MHz, DMSO-d6) δ 9.22 (br,2H), 8.85 (m, 1H), 8.63 (m, 1H), 8.16 (s, 1H), 8.09 (m, 1H), 8.07 (m,1H), 7.85 (br, 1H), 7.27 (m, 1H), 6.19 (s, 1H), 2.84 (d, 3H), 2.20 (s,3H), 2.15 (s, 3H); ESMS m/z 467.1 (M + H+). 0.089 5

5-chloro-N2-(2-fluoro-5-methyl-4-(6-methylpyridin-3-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine ESMS m/z 424.1 (M + H+). 0.137 6

5-chloro-N2-(2-fluoro-5-methyl-4-(pyridin-2-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMS m/z410.1 (M + H+). 0.294 7

5-chloro-N2-(2-fluoro-5-methyl-4-(quinolin-3-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMS m/z460.1 (M + H+). 0.579 8

5-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2- methylphenyl)pyridin-2-ol ESMSm/z 426.1 (M + H+). 0.055 9

5-chloro-N2-(2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine ESMS m/z 424.1 (M + H+). 0.094 10

5-chloro-N2-(2-fluoro-5-methyl-4-(thiophen-3-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMS m/z415.1 (M + H+). 0.833 11

5-chloro-N2-(2-fluoro-4-(furan-3-yl)-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMSm/z 399.1 (M + H+). 0.683 12

5-chloro-N2-(2,5-dimethyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine 1H NMR (400 MHz, DMSO-d6) δ 9.67 (br, 2H),9.30 (br, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.68 (s, 1H), 7.31 (s, 1H),7.28 (s, 1H), 6.97 (s, 1H), 3.89 (s, 3H), 2.33 (s, 3H), 2.18 (s, 3H),2.07 (s, 3H); ESMS m/z 409.1 (M + H+) 0.025 13

5-chloro-N2-(2-fluoro-4-(furan-3-yl)-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMSm/z 406.1 (M + H+). 0.029 14

5-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)-N-methylpicolinamideESMS m/z 463.2 (M + H+). 0.015 15

5-chloro-N2-(2,5-dimethyl-4-(2-methylpyridin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMS m/z420.2 (M + H+). 0.039 16

5-chloro-N2-(2,5-dimethyl-4-(6-methylpyridin-3-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMS m/z420.2 (M + H+). 0.030 17

N2-(4-(1H-imidazol-2-yl)-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine- 2,4-diamine 1H NMR (400MHz, DMSO-d6) δ 9.01 (br, 2h), 8.83 (s, 1h), 8.12 (s, 1H), 7.83 (s, 2H(,7.78 (s, 1H), 7.45 (s, 1H), 6.20 (s, 1H), 2.30 (s, 3H), 2.29 (s, 3H),2.15 (s, 3H); ESMS m/z 395 (M + H+). 0.068 18

5-chloro-N2-(2,5-dimethyl-4-(3-methylisoxazol-5-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine 1H NMR(400 MHz, DMSO-d6) δ 9.3 (br, 2H), 9.0 (br, 1H), 8.13 (s, 1H), 7.58 (s,1H), 7.55 (s, 1H), 6.64 (s, 1H), 6.07 (s, 1H), 2.39 (s, 3H), 2.30 (s,3H), 2.25 (s, 3H), 2.09 (s, 3H); ESMS m/z 410.1 (M + H+). 0.276 19

5-chloro-N2-(2-fluoro-4-(1H-imidazol-2-yl)-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMSm/z 399.1 (M + H+). 0.288 20

5-chloro-N2-(2,5-dimethyl-4-(oxazol-5-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine 1H NMR (400 MHz,DMSO-d6) δ 9.40 (br, 2H), 9.14 (br 1H), 8.47 (s, 1H) 8.14 (s, 1H), 7.56(s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 6.03 (s, 1H), 2.39 (s, 3H), 2.24(s, 3H), 2.06 (s, 3H); ESMS m/z 396.1 (M + H+). 0.109 21

5-chloro-N2-(2-methoxy-5-methyl-4-(oxazol-5-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMS m/z412.1 (M + H+). 0.169 22

5-chloro-N2-(2,5-dimethyl-4-(3-methyl-1H-pyrazol-5-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine ESMS m/z 409.2 (M + H+). 0.166 23

5-chloro-N2-(2,5-dimethyl-4-(3-methylisoxazol-5-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine 1H NMR(400 MHz, DMSO-d6) δ 9.3 (br, 2H), 9.0 (br, 1H), 8.13 (s, 1H), 7.58 (s,1H), 7.55 (s, 1H), 6.64 (s, 1H), 6.07 (s, 1H), 2.39 (s, 3H), 2.30 (s,3H), 2.25 (s, 3H), 2.09 (s, 3H); ESMS m/z 410.1 (M + H+). 24

5-chloro-N2-(2,5-dimethyl-4-(2-methylthiazol-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine 1H NMR(400 MHz, DMSO-d6) 9.56 (br, 2H), 9.25 (br, 1H), 8.14 (s, 2H), 7.56 (s,1H), 7.53 (s, 1H), 7.37 (s, 1H), 6.07 (s, 1H), 2.71 (s, 3H), 2.37 (s,3H), 2.21 (s, 3H), 2.09 (s, 3H); ESMS m/z 426.1 (M + H+). 0.106 25

5-chloro-N2-(2,5-dimethyl-4-(1-methyl-1H-imidazol-2-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine ESMS m/z 409.2 (M + H+). 0.071 26

N2-(4-(1H-imidazol-2-yl)-2,5-dimethylphenyl)-5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine- 2,4-diamine 1H NMR (400MHz, DMSO-d6) 9.01 (br, 2h), 8.83 (s, 1h), 8.12 (s, 1H), 7.83 (s, 2H(,7.78 (s, 1H), 7.45 (s, 1H), 6.20 (s, 1H), 2.30 (s, 3H), 2.29 (s, 3H),2.15 (s, 3H); ESMS m/z 395.1 (M + H+). 27

5-chloro-N2-(5-fluoro-2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine ESMS m/z 412.8 (M + H⁺) 0.549 28

1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)ethanoneO-2-hydroxyethyl oxime ESMS m/z 430.2 (M + H⁺) 0.141 29

1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)ethanone oxime ESMS m/z386.1 (M + H⁺) 0.051 30

4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-N,N,2,5- tetramethylbenzamide ESMS m/z400.2 (M + H⁺) 0.539 31

4-(5-chloro-4-(5-methyl-1H-pyrazol-3- ylamino)pyrimidin-2-ylamino)-N-(2-dimethylamino)ethyl)-2,5-dimethylbenzamide ESMS m/z 443.2 (M + H⁺) 0.65932

(4-(5-chloro-4-(5-methyl-1H-pyrazol-3- ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)(morpholino)methanone ESMS m/z 442.2 (M + H⁺) 0.451 33

4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)cyclohexanone oximeESMS m/z 440.2 (M + H⁺) 0.015 34

1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)ethanone O-methyl oximeESMS m/z 400.2 (M + H⁺) 0.269 35

1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)ethanone O-2-(dimethylamino)ethyl oxime ESMS m/z 457.2 (M + H⁺) 0.121 36

1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)ethanone O-2-morpholinoethyl oxime ESMS m/z 499.2 (M + H⁺) 0.187 37

Trans-5-chloro-N2-(2,5-dimethyl-4-(4-morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine ESMS m/z 496.3 (M + H⁺) 0.011 38

Cis-5-chloro-N2-(2,5-dimethyl-4-(4-morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine ESMS m/z 496.3 (M + H⁺) 0.009 39

5-chloro-N2-(2,5-dimethyl-4- (morpholinomethyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine ESMS m/z 459.2 (M + H⁺) 0.151 40

4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2- ylamino)phenyl)cyclohexanoneESMS m/z 459.2 (M + H⁺) 0.049 41

trans-4-(2,5-dimethyl-4-(4-(5-methyl-1H- pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2- ylamino)phenyl)cyclohexanol ESMS m/z 461.2(M + H⁺) 0.025 42

Cis-4-(2,5-dimethyl-4-(4-(5-methyl-1H- pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2- ylamino)phenyl)cyclohexanol ESMS m/z 461.2(M + H⁺) 0.053 43

Cis-5-chloro-N2-(2,5-dimethyl-4-(4-(pipcridin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine ESMS m/z 494.3 (M + H⁺)0.008 44

Trans-5-chloro-N2-(2,5-dimethyl-4-(4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine ESMS m/z 494.3 (M + H⁺)0.007 45

trans-4-(4-(5-chloro-4-(5-rnethyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)cyclohexanol ESMS m/z427.2 (M + H⁺) 0.014 46

Trans-5-chloro-N2-(4-(4- (cyclopropylamino)cyclohexyl)-2,5-dimethylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamineESMS m/z 466.2 (M + H⁺) 0.016 47

Cis-5-chloro-N2-(4-(4- (cyclopropylamino)cyclohexyl)-2,5-dimethylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamineESMS m/z 466.2 (M + H⁺) 0.017 48

Cis-5-chloro-N2-(2-fluoro-5-methyl-4-(4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine ESMS m/z 498.3 (M + H⁺)0.021 49

Trans-5-chloro-N2-(2-fluoro-5-methyl-4-(4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine ESMS m/z 498.3 (M + H⁺)0.040 50

Trans-5-chloro-N2-(2-fluoro-5-methyl-4-(4-morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine ESMS m/z 500.2 (M + H⁺) 0.031 51

Cis-5-chloro-N2-(2-fluoro-5-methyl-4-(4-morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine ESMS m/z 500.2 (M + H⁺) 0.400 52

Cis-5-chloro-N2-(2-fluoro-5-methyl-4-(4-(4-methylpiperazin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine ESMS m/z 513.3 (M +H⁺) 0.024 53

Trans-5-chloro-N2-(2-fluoro-5-methyl-4-(4-(4-methylpiperazin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine ESMS m/z 513.3 (M +H⁺) 0.025 54

(S)-1-((Cis)-4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)cyclohexyl)pyrrolidin- 3-ol ESMS m/z 500.2 (M +H⁺) 0.016 55

(S)-1-((Trans)-4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)cyclohexyl)pyrrolidin- 3-ol ESMS m/z 500.2 (M +H⁺) 0.032 56

5-chloro-N2-(4-((cis)-4- (diethylamino)cyclohexyl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMSm/z 486.3 (M + H⁺) 0.025 57

5-chloro-N2-(4-((trans)-4- (diethylamino)cyclohexyl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine ESMSm/z 486.3 (M + H⁺) 0.031 58

5-chloro-N2-(2-fluoro-5-methyl-4-((cis)-4-(piperazin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine ESMS m/z 499.2 (M + H⁺)0.017 59

5-chloro-N2-(2-fluoro-5-methyl-4-((trans)-4-(piperazin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine ESMS m/z 499.2 (M + H⁺)0.039 60

N2-(2,5-dimethyl-4-((cis)-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine- 2,4-diamine ESMS m/z 528.3(M + H⁺) 0.004 61

N2-(2,5-dimethyl-4-((trans)-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine- 2,4-diamine ESMS m/z 528.3(M + H⁺) 0.003 62

N2-(2-fluoro-5-methyl-4-((cis)-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine- 2,4-diamine ESMS m/z 532.3(M + H⁺) 0.018 63

N2-(2-fluoro-5-methyl-4-((trans)-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine- 2,4-diamine ESMS m/z 532.3(M + H⁺) 0.016 64

N2-(2-fluoro-5-methyl-4-((cis)-4-morpholinocyclohexyl)phenyl)-N4-(5-methyl- 1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine ESMS m/z 534.3 (M + H⁺) 0.05 65

N2-(2-fluoro-5-methyl-4-((trans)-4-morpholinocyclohexyl)phenyl)-N4-(5-methyl- 1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine ESMS m/z 534.3 (M + H⁺) 0.032 66

N2-(2,5-dimethyl-4-((cis)-4- morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine ESMS m/z530.3 (M + H⁺) 0.014 67

N2-(2,5-dimethyl-4-((trans)-4-morpholinocyclohexyl)phenyl)-N4-(5-methyl- 1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine ESMS m/z 530.3 (M + H⁺) 0.009 68

(3S,4S)-1-((cis)-4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexyl)pyrrolidine-3,4- diol ESMS m/z 550.3 (M + H⁺)0.12 69

(3S,4S)-1-((trans)-4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexyl)pyrrolidine-3,4- diol ESMS m/z 550.3 (M + H⁺)0.302 70

(3R,4R)-1-((trans)-4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexyl)pyrrolidine-3,4- diol ESMS m/z 550.3 (M + H⁺)0.248 71

(3R,4R)-1-((cis)-4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexyl)pyrrolidine-3,4- diol ESMS m/z 550.3 (M + H⁺)0.109 72

Trans-4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2- methylphenyl)cyclohexanolESMS m/z 431.2 (M + H⁺) 0.099 73

Cis-4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2- methylphenyl)cyclohexanol ESMSm/z 431.2 (M + H⁺) 0.032 74

5-chloro-N2-(2,5-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine ESMS m/z 460.2 (M + H⁺)0.087 75

5-chloro-N2-(2,5-dimethyl-4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine ESMS m/z 474.2 (M +H⁺) 0.054

Example 146-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-(piperidin-4-yl)isoindolin-1-one(79)

To the solution of tert-butyl4-(6-amino-5-fluoro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate(Intermediate 20, 18 mg, 0.05 mmol) and2,5-dichloro-4-(5-methyl-1H-pyrazol-3-yl)pyrimidine (12 mg, 0.05 mmol)in 1 mL of i-PrOH was added 5 drops of conc. aqueous HCl. The reactionmixture was heated at 150° C. in a microwave reactor for 20 min,followed by concentration and purification with preparative RP-HPLC toafford6-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-(piperidin-4-yl)isoindolin-1-one;ESMS m/z 457.2 (M+H⁺).

Example 156-(5-chloro-4-(5-methylisoxazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-(piperidin-4-yl)isoindolin-1-one(80)

To the solution of tert-butyl4-(6-amino-5-fluoro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate (35mg, 0.1 mmol) and 5-chloro-4-(5-methylisoxazol-3-yl)pyrimidin-2-amine(25 mg, 0.1 mmol) in 1 mL of i-PrOH was added 5 drops of conc. aqueousHCl. The reaction mixture was heated at 150° C. in microwave reactor for20 min, followed by concentration and purification with preparativeRP-HPLC to afford6-(5-chloro-4-(5-methylisoxazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-(piperidin-4-yl)isoindolin-1-one;ESMS m/z 458.1 (M+H⁺).

Example 162-(4-(6-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-4-methylpyridin-3-yl)piperidin-1-yl)acetamide(84)

Step 1: To a mixture of 5-bromo-4-methylpyridin-2-amine (200 mg, 1.07mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(370 mg, 1.2 mmol) and sodium carbonate (400 mg, 1.28 mmol) in DMF/H₂O(8/2 mL) was added tetrakis(triphenylphosphine) palladium (0) (62 mg, 5%mmol). The reaction tube is sealed, the mixture was purged with N₂ for 3min and then heated at 100° C. under N₂ for overnight. The reaction wascooled to room temperature and poured into saturated aqueous ammoniachloride solution. The crude reaction mixture was extracted with ethylacetate (3×15 mL). The organic extracts were combined, washed with brineand concentrated. The crude product was purified with silica gel columnchromatography (80% ethyl acetate in hexanes) to afford tert-butyl4-(6-amino-4-methylpyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylateas a yellow oil. The obtained oil was dissolved in methanol (20 mL). Tothe solution was added Pd/C (10% w/w). The reaction mixture was degassedand purged with H₂ for several times and then stirred under 1 atm. H₂overnight. The mixture was filtered and concentrated to affordtert-butyl 4-(6-amino-4-methylpyridin-3-yl)piperidine-1-carboxylate as ayellow solid; ESMS m/z 236 (M−56+H⁺).

Step 2: To a mixture of2,5-dichloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine(150 mg, 0.45 mmol), tert-butyl4-(6-amino-4-methylpyridin-3-yl)piperidine-1-carboxylate (120 mg, 0.41mmol), Xantphos (24 mg, 0.04 mmol) and cesium carbonate (270 mg, 0.82mmol) in THF (4 mL) was added palladium acetate (5 mg, 0.02 mmol). Themixture was purged with nitrogen and the tube was sealed. The mixturewas heated in an oil bath at 100° C. for 5 h. The mixture was filteredand concentrated. The residue was purified with silica chromatography(70% ethyl acetate in hexanes) to afford tert-butyl4-(6-(5-chloro-4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-4-methylpyridin-3-yl)piperidine-1-carboxylateas a yellow solid; ESMS m/z 583 (M+H⁺).

Step 3: To a solution of tert-butyl4-(6-(5-chloro-4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-4-methylpyridin-3-yl)piperidine-1-carboxylatein DCM (1 mL), was added TFA (1 mL). The mixture was stirred for 1 h andconcentrated to afford5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-methyl-5-(piperidin-4-yl)pyridin-2-yl)pyrimidine-2,4-diamineas brownish oil. The product was used directly for subsequent reactionswithout further purification.

Step 4: To a mixture of5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-methyl-5-(piperidin-4-yl)pyridin-2-yl)pyrimidine-2,4-diamine(50 mg, 0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL),was added 2-bromo-acetamide (25 mg, 0.18 mmol). The mixture was stirredat room temperature for 2 hours. The reaction was filtered and thefiltrate was purified by RP-HPLC to afford2-(4-(6-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-4-methylpyridin-3-yl)piperidin-1-yl)acetamideas a white solid; ¹H NMR (400 MHz, MeOD-d₄) δ 8.30 (s, 1H), 8.21 (s,1H), 7.28 (s, 1H), 6.19 (s, 1H), 4.0 (s, 2H), 3.80-3.73 (m, 2H),3.33-3.21 (m, 3H), 2.61 (s, 3H), 2.37 (s, 3H), 2.37-2.32 (m, 2H),2.20-2.16 (m, 2H); ESMS m/z 456.2 (M+H⁺).

Example 175-chloro-N⁴-(5-methyl-1H-pyrazol-3-yl)-N²-(4-(piperidin-4-yl)naphthalene-1-yl)pyrimidine-2,4-diamine(85)

A mixture of2,5-dichloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine(202.7 mg, 0.62 mmol),tert-butyl-4-(4-aminonaphthalen-1-yl)piperidine-1-carboxylate (202.0 mg,0.62 mmol), Xantophos (35.9 mg, 0.062 mmol), padallium acetate (II) (7.0mg, 0.031 mmol), and cesium carbonate (40.3 mg, 0.12 mmol) in 5.0 mL ofTHF was heated at 150° C. in a microwave reactor for 25 min. Thereaction mixture was filtered and the filtrate was concentrated invacuo. The crude product was dissolved in 5 mL of DCM and 4 mL of TFA.This reaction mixture was stirred at room temperature for 2 h followedby concentration in vacuo. The crude product is purified by RP-HPLC toafford5-chloro-N⁴-(5-methyl-1H-pyrazol-3-yl)-N²-(4-(piperidin-4-yl)naphthalene-1-yl)pyrimidine-2,4-diamine;ESMS m/z 434.2 (M+H⁺)

Example 182-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)naphthalene-1-yl)piperidin-1-yl)acetamide(86)

A mixture of5-chloro-N⁴-(5-methyl-1H-pyrazol-3-yl)-N²-(4-(piperidin-4-yl)naphthalene-1-yl)pyrimidine-2,4-diamine(30.8 mg, 0.07 mmol), 2-bromoacetamide (19.6 mg, 0.14 mmol) andtriethylamine (30.0 μL, 0.21 mmol) in 2 mL of DMF was heated at 130° C.in a microwave reactor for 20 min. The crude product was purified byRP-HPLC to afford2-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)naphthalene-1-yl)piperidin-1-yl)acetamide;ESMS m/z 491.2 (M+H⁺).

Example 193-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)naphthalen-1-yl)piperidin-1-yl)-1,1,1-trifluoropropan-2-ol(88)

A mixture of5-chloro-N⁴-(5-methyl-1H-pyrazol-3-yl)-N²-(4-(piperidin-4-yl)naphthalene-1-yl)pyrimidine-2,4-diamine(30.8 mg, 0.07 mmol) and 2-(trifluoromethyl)oxirane (39.2 mg, 0.35 mmol)in 1 mL of DMF was stirred at room temperature overnight. The crudemixture was purified by RP-HPLC to give3-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)naphthalen-1-yl)piperidin-1-yl)-1,1,1-trifluoropropan-2-ol;ESMS m/z 546.2 (M+H⁺).

The following compounds in Table 2 are obtained by repeating theprocedures described in examples above and using appropriate startingmaterials.

TABLE 2 IGF1R Ba/F3 IC50 STRUCTURE NMR or ESMS (uM) 76

ESMS m/z 456.2 (M + H⁺). 1.792-(4-(6-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2-methylpyridin-3-yl)piperidin-1-yl)acetamide 77

ESMS m/z 492.2 (M + H⁺). 3.3 2-(4-(8-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)isoquinolin-5-yl)piperidin- 1-yl)acetamide78

ESMS m/z 541.2 (M + H⁺). 0.4125-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(5-(1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)quinolin-8-yl)pyrimidine-2,4-diamine 79

ESMS m/z 457.2 (M + H⁺). 6.4 6-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-(piperidin-4-yl)isoindolin-1-one 80

ESMS m/z 458.1 (M + H⁺). 2.656-(5-chloro-4-(5-methylisoxazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-(piperidin-4-yl)isoindolin-1-one 81

ESMS m/z 400.1 (M + H⁺). 2.30 6-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoroisoindolin-1-one 82

ESMS m/z 374.1 (M + H⁺). 2.63 6-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoroisoindolin-1-one 83

ESMS m/z 367.1 (M + H⁺). 1.455-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(3-methylcinnolin-5-yl)pyrimidine-2,4-diamine 84

ESMS m/z 456.2 (M + H⁺). 0.5252-(4-(6-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-4-methylpyridin-3-yl)piperidin-1-yl)acetamide 85

ESMS m/z 434.2 (M + H⁺) 0.4935-chloro-N4-(5-methyl-1H-pyrazol-3-yl)-N2-(4-(piperidin-4-yl)naphthalen-1-yl)pyrimidine-2,4- diamine 86

ESMS m/z 491.2 (M + H⁺) 0.1072-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)naphthalen-1- yl)piperidin-1-yl)acetamide 87

ESMS m/z 505.2 (M + H⁺) 0.0822-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)naphthalen-1-yl)piperidin-1-yl)-N-methylacetamide 88

ESMS m/z 546.2 (M + H⁺) 0.3463-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)naphthalen-1-yl)piperidin-1-yl)-1,1,1-trifluoropropan-2-ol 89

ESMS m/z 398.2 (M + H⁺) 0.0885-chloro-N2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[diazepin-7-yl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

Assays

The IC₅₀ of a drug may be determined constructing a dose-response curveand examining the effect of different concentrations of antagonist onreversing agonist activity. IC₅₀ values may be calculated for a givenantagonist by determining the concentration needed to inhibit half ofthe maximum biological response of the agonist. To calculate IC₅₀values, a series of dose-response data (e.g., drug concentrations x1,x2, . . . , xn and growth inhibition y1, y2, . . . , yn, the values of yare in the range of 0-1) is generated. IC₅₀ values may be determined bya computer-aided system using the formula:

y=D+((A−D)/(1+10^((x-log(IC50)B))

where A is the ratio of growth inhibition between lowest drugconcentration and control; B is the slope of sigmoidal curvel; and D isthe ratio of growth inhibition between highest drug concentration andcontrol.

The IC₅₀ value is given as that concentration of the test compound thatresults in growth inhibition that is 50% lower than that obtained usingthe control without inhibitor. The compounds of the invention in freeform or in pharmaceutically acceptable salt form may exhibit valuablepharmacological properties, for example, as indicated by the in vitrotests described in this application. In general, compounds of theinvention have IC₅₀ values from 1 nM to 10 μM. In some examples,compounds of the invention have IC₅₀ values from 0.01 μM to 5 μM. Inother examples, compounds of the invention have IC₅₀ values from 0.01 μMto 1 μM, or more particularly from 1 nM to 1 μM. In yet other examples,compounds of the invention have IC₅₀ values of less than 1 nM or morethan 10 μM. The compounds of the invention may exhibit a percentageinhibition of greater than 50%, or in other embodiments, may exhibit apercentage inhibition greater than about 70%, against IGF-1R at 10 μM.

Ba/F3 Cell Line Panel and Reagents

Ba/F3 is a murine IL-3-dependent pro-B lymphoma cell line. ParentalBa/F3 cells are used to generate a panel of sublines whose proliferationand survival is rendered IL-3-independent by stable transduction withindividual tyrosine kinases activated by fusion with the amino-terminalportion of TEL (amino acid 1-375) or BCR. In order to generate Ba/F3cell lines transformed by Tel-Tyrosine Kinase (TK) fusions, parentalBa/F3 cells are infected with a retrovirus harboring each TEL-fusionkinase and subjected to puromycin selection and IL-3 withdrawal toobtain IL-3-independent, transformed Ba/F3 cells.

Each transformed Ba/F3 cells are cultured in RPMI-1640 media (Gibco Cat#11875093, Carlsbad, Calif.) supplemented with 10% FBS (Hyclone Cat#SV30014.03, Logan, Utah), 4.5 g/L glucose (Sigma #G5400, St.Louis,Mo.), 1.5 g/L sodium bicarbonate (Biowhittaker #17-613E, Walkersville,Md.) and Pen/Strep (Gibco #10378-016, Carlsbad, Calif.). Cells aresplitted twice weekly.

Ba/F3 Cell Viability Inhibition Assay

The potency of test compounds against various Tel-TK transformed Ba/F3lines is determined as follows. Exponentially growing BaF3 Tel-TK cellsare diluted in fresh medium to 75,000 cells/mL and seeded into 384-wellplates (3750 cells/well) at 50 μL/well using a gill liquid dispenser(BioTek, Winooski, Vt., USA). Duplicate plates are run for each cellline. Test and control compounds are serially diluted with DMSO andarrayed in a polypropylene 384-well plate. 50 nL of compound istransferred into the assay plates using a pin-transfer device, and theplates are incubated at 37° C. (5% CO₂) for 48 hours. 25 μL Britelite(Perkin Elmer) is added and luminescence is quantified using Analyst GT(Molecular Devices). Custom curve-fitting software is used to produce alogistic fit of percent cell viability as a function of the logarithm ofinhibitor concentration. The IC₅₀ is interpolated as the concentrationof compound needed to reduce cell viability to 50% of a DMSO control.Parental Ba/F3 cells that are maintained and cultured in presence ofIL-3 (1 ng/ml in final) are diluted in fresh medium containing IL-3 (1ng/ml in final) to 75,000 cells/mL following the same procedure asdescribed above.

Enzymatic HTRF Assay

IGF-1R and INSR (insulin receptor) are purchased from Upstate. Followingreagents are prepared in-house; 10× kinase buffer (KB) (200 mM Tris (pH7.0), 100 mM MgCl₂, 30 mM MnCl₂, 50 nM NaVO₄), 10 mM ATP, 100 mg/ml BSA,0.5 M EDTA, 4 M KF. Proxiplate-384 from Perkin-Elmer is used for set upassay. All the HTRF reagents including substrate (Biotin-poly-GT(61GT0BLB), Mab PT66-K, (61T66KLB), Streptavidin-XL^(ent) (611SAXLB))are purchased from CIS-US, Inc.

The substrate/ATP mix is prepared by adding ATP (final concentration, 3μM) and biotinylated poly-GT (final concentration, 10 ng/μl) into 1× KB,and dispensed into Proxiplate-384 at 5 μl/well using μFill (Bio-TEK).Serially diluted compounds (in DMSO) are transferred into plate using 50nL pinhead. 5 μL of prepared Enzyme mix (enzyme (final concentration, 5ng/μl), mixed with BSA and DTT in 1× KB) is added to initiate kinasereaction using μFill (Bio-TEK). Assay plate is incubated at roomtemperature for 2 hours. Detection mix is prepared by adding both MabPT66-K and Streptavidin-XL^(ent) into 0.5× KB solution containing KF(final concentration, 125 mM), EDTA (final concentration, 50 mM) and BSA(final concentration, 100 μg/ml) in. At the end of reaction, 10 μL ofdetection mix is added and incubated for 30 minutes at room temperaturebefore measurement. HTRF signal is detected using Analyst-GT (molecularDevices).

Cancer Cell Proliferation Inhibition Assay

For luciferizing cancer cell line, each cell line is transduced byampholytic retrovirus carrying both luciferase gene andpuromycin-resistant gene whose expression is driven by LTR. Briefly, theretroviral vector pMSCV-Puro-Luc is transfected into Phoenix cell lineusing Fugene6 (Roche) according to manufacturer's instruction. Two daysafter transfection, supernatant containing virus is harvested andfiltered with 0.2 μm filter. Harvested virus is used immediately orstored at −80′C. For infection, cultured cancer cells are harvested andplated (5×10⁵ cells/well in 1 ml medium) on 6-well tissue culture plate.For each well, 3 ml virus supernatant is added together with 400 μl FBS,40 μl 1 M HEPES (pH8.0) and 4 μl of polybrene (10 μg/ml, Specialtymedia). The plate is centrifuged down for 90 minutes at 2500 rpm forspin-infection and is transferred into an incubator for overnightinfection. Next day, infected cell line is transferred into T-75 flaskcontaining fresh medium and incubated for one day. Two days afterinfection, puromycin is added at the final concentration of 1 μg/ml tobegin selection. Within 1-2 weeks, puromycin-resistant cell line isestablished after at least two subsequent splits and is preserved asluciferized stock.

Each cell line is harvested while in log phase growth by trypsinizationand diluted in respective media to appropriate density prior to plating.Cells are dispensed using μFill (BioTeK) at 50 μl/well into white walledclear bottom plates (Greiner—custom for GNF). Cells are then placed in37° C. incubator supplying 5% CO2 overnight. Compounds are transferredusing 50nL/well Pintool technology via Platemate (Matrix). Assay platesare then placed back into the incubator for 3 days. On the third dayfollowing compound transfer, BRITELITE® (Perkin Elmer, diluted accordingto manufacturer's suggestion) is added to assay plates and read onAnalyst GT (Molecular Devices) or Envision (Perkin Elmer). Raw data isgenerated in RLU.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound of Formula (1):

or a physiologically acceptable salt thereof;

wherein W is or W′; W′ is pyridyl, isoquinolinyl, quinoliny,naphthalenyl, cinnolin-5-yl or [3-(C₁₋₆alkyl)-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl], each of which isoptionally substituted with 1-3 R⁹; and said pyridyl, isoquinolinyl,quinolinyl and napthalenyl are each substituted on a ring carbon with

X is —C(R)═N—O—R⁷, C(O)NRR⁷, C(O)NR—(CR₂)_(n)—NRR⁷, —(CR₂)_(p)NRRwherein two R groups together with N in NRR form a 5-6 membered ringcontaining 1-3 heteroatoms selected from N, O and S and optionallysubstituted with 1-3 R⁹, or a C₅₋₇ carbocycle optionally substitutedwith oxo, ═N—OH or R⁹; or X is quinolinyl,(1,2,3,4-tetrahydroisoquinolin-6-yl) or a 5-6 membered heteroaryl having1-3 heteroatoms selected from N, O and S, each of which is optionallysubstituted with 1-3 R⁹; R¹ is halo, C₁₋₆ alkyl, or a halo-substitutedC₁₋₆ alkyl; R² is a 5-6 membered heteroaryl having 1-3 heteroatomsselected from N, O and S, and is optionally substituted with C₁₋₆ alkyl,C₁₋₆ haloalkyl or C₃₋₇ cycloalkyl; each R³ is H; R⁴ is halo, hydroxyl,C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-substituted C₁₋₆ alkyl, halo-substitutedC₁₋₆ alkoxy, cyano or C(O)O₀₋₁R⁸; R⁵ is H or

R⁶ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which may beoptionally substituted with halo and/or hydroxyl groups; —(CR₂)_(p)—OR⁷,—(CR₂)_(p)—CH(OH)C_(t)F_(2t+1) wherein t is 1-3, (CR₂)_(p)—CN;(CR₂)_(p)—NR (R⁷), —(CR₂)_(p)—C(O)OR⁷, (CR₂)_(p)NR(CR₂)_(p)OR⁷,(CR₂)_(p)NR-L-C(O)R⁸, C(O)(CR₂)_(q)OR⁸, —C(O)O—(CR₂)_(p)—NRR⁷, —C(O)—(CR₂)_(p)—OR⁷, L-Y, -L-C(O)R⁷, -L-C(O)—NRR⁷, -L-C(O)—NR— (CR₂)_(p)—NRR⁷,-L-C(O)NR(CR₂)_(p)OR⁷, -L-C(O)— (CR₂)_(q)—NR—C(O)—R⁸,-L-C(O)NR(CR₂)_(p)SR⁷, -L-C(O)NR(CR₂)_(p)S(O)₁₋₂R⁸, -L-S(O)₂R⁸,-L-S(O)₂—(CR₂)_(q)—NRR⁷, -L-S(O)₂NR(CR₂)_(p)NR(R⁷) or-L-S(O)₂NR(CR₂)_(p)OR⁷; alternatively, R⁶ is a radical selected fromformula (a), (b), (c) or (d):

R¹⁰ is O, S, NR¹⁷ wherein R¹⁷ is H, C₁₋₆ alkyl, SO₂R^(8a) or CO₂R^(8a);R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently selected from H; C₁₋₆alkoxy; C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which may beoptionally substituted with halo, amino or hydroxyl groups; or R¹¹ andR¹², R¹² and R¹⁵, R¹⁵ and R¹⁶, R¹³ and R¹⁴, or R¹³ and R¹⁵ together withthe atoms to which they are attached may form a 3-7 membered saturated,unsaturated or partially unsaturated ring containing 1-3 heteroatomsselected from N, O and S, and optionally substituted with oxo and 1-3 R⁹groups; L is (CR₂)₁₋₄ or a bond; Y is C₃₋₇ carbocyclic ring, C₆₋₁₀ aryl,or a 5-10 membered heteroaryl or 4-10 membered heterocyclic ring, eachof which is optionally substituted with 1-3 R⁹ groups; R⁷, R⁸ and R^(8a)are independently C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each ofwhich may be optionally substituted with halo, NRR^(7a), hydroxyl orcyano; (CR₂)_(q)Y or C₁₋₆ alkoxy; or R⁷ is H; R⁹ is R⁴, C(O)NRR⁷ orNRR⁷; R and R^(7a) are independently H or C₁₋₆ alkyl; R and R⁷ togetherwith N in each NRR⁷, and R and R^(7a) together with N in NRR^(7a) mayform a 5-6 membered ring containing 1-3 heteroatoms selected from N, Oand S, and optionally substituted with oxo and 1-3 R⁴ groups; m is 2-4;n and p are independently 1-4; and q is 0-4.
 2. The compound of claim 1,wherein R² is pyrazolyl or isoxazolyl, each of which is substituted withC₁₋₆ alkyl or C₃₋₇ cycloalkyl.
 3. The compound of claim 1, wherein saidcompound is of Formula (2):

wherein W is W′; W′ is pyridyl optionally substituted with C₁₋₆ alkyl,isoquinolinyl, quinolinyl, naphthalenyl, cinnolin-5-yl optionallysubstituted with C₁₋₆ alkyl or [3-(C₁₋₆alkyl)-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7yl]; and said pyridyl,isoquinolinyl, quinolinyl and napthalenyl are each substituted on a ringcarbon with

R⁶ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl, each of which may beoptionally substituted with halo, amino, hydroxyl or alkoxy;—(CR₂)_(p)—CH(OH)C_(t)F_(2t+1) wherein t is 1, -L-C(O)—NRR⁷ or-L-S(O)₂R⁸; L is (CR₂)₁₄; R and R⁷ are independently H or C₁₋₆ alkyl; R⁸is C₁₋₆ alkyl; and R¹ and R³ are as defined in claim
 1. 4. The compoundof claim 1, wherein said compound is of Formula (3)

wherein Z is NH or O; R⁴ is halo or C₁₋₆ alkyl; R⁵ is H or

R⁶ is H; and R¹ and R³ are as defined in claim
 1. 5. The compound ofclaim 1, wherein said compound is of Formula (4):

wherein one of R^(4a), R^(4b) and R^(4c) is H and the others areindependently halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-substituted C₁₋₆ alkylor halo-substituted C₁₋₆ alkoxy; and X is as defined in claim
 1. 6. Thecompound of claim 5, wherein X is —C(R)═N—O—R⁷, C(O)NRR⁷,C(O)NR—(CR₂)_(n)—NRR⁷ or —(CR₂)_(p)NRR wherein two R groups togetherwith N in NRR form morpholinyl; R⁷ is H or C₁₋₆ alkyl optionallysubstituted with hydroxyl or NRR^(7a); each R is H or C₁₋₆ alkyl; R andR⁷ together with N in each NRR⁷ and R and R^(7a) together with N inNRR^(7a) may form a 5-6 membered ring containing 1-2 heteroatomsselected from N, O and S; and n and p are as defined in claim
 1. 7. Thecompound of claim 6, wherein X is quinolinyl,(1,2,3,4-tetrahydroisoquinolin-6-yl) or a 5-6 membered heteroarylselected from pyrazolyl, pyridyl, thiophenyl, furanyl, imidazolyl,isoxazolyl, oxazolyl or thiaxolyl, each of which is optionallysubstituted with C₁₋₆ alkyl, hydroxyl, or C(O)NRR⁷; R⁷ is H or C₁₋₆alkyl; and R is H or C₁₋₆ alkyl.
 8. The compound of claim 1, whereinsaid compound is of Formula (5):

wherein one of R^(4a), R^(4b) and R^(4c) is H and the others areindependently halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-substituted C₁₋₆ alkylor halo-substituted C₁₋₆ alkoxy; Ring E is a C₆ carbocycle optionallysubstituted with oxo, ═N—OH or R⁹; R⁹ is hydroxyl or NRR⁷; R is H orC₁₋₆ alkyl; R⁷ is C₁₋₆ alkyl or (CR₂)_(q)Y and Y is C₃ cycloalkyl;alternatively, R and R⁷ together with N in NRR⁷ forms morpholinyl,piperidinyl, piperazinyl, (C₁₋₆ alkyl)-piperazinyl, or pyrrolidinyl,each of which is optionally substituted with hydroxyl; and R¹ and R³ areas defined in claim
 1. 9. The compound of claim 1, wherein R^(4b) is H.10. The compound of claim 1, wherein R^(4a) and R^(4c) are independentlyhalo, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-substituted C₁₋₆ alkyl orhalo-substituted C₁₋₆ alkoxy.
 11. The compound of claim 1, wherein R¹ ischloro or a halo-substituted C₁₋₆ alkyl.
 12. The compound of claim 1,wherein each R³ is H.
 13. The compound of claim 1, wherein said compoundis selected from the group consisting of

5-chloro-N2-(2-fluoro-5-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

5-chloro-N2-(2,5-dimethyl-4- (morpholinomethyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

5-chloro-N2-(2-fluoro-5-methyl-4-(pyridin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2- ylamino)phenyl)cyclohexanone

5-chloro-N2-(2-fluoro-5-methyl-4-(pyridin-3-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

trans-4-(2,5-dimethyl-4-(4-(5-methyl-1H- pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2- ylamino)phenyl)cyclohexanol

5-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)-N-methylpicolinamide

Cis-4-(2,5-dimethyl-4-(4-(5-methyl-1H- pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2- ylamino)phenyl)cyclohexanol

5-chloro-N2-(2-fluoro-5-methyl-4-(6-methylpyridin-3-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

Cis-5-chloro-N2-(2,5-dimethyl-4-(4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine

5-chloro-N2-(2-fluoro-5-methyl-4-(pyridin-2-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

Trans-5-chloro-N2-(2,5-dimethyl-4-(4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine

5-chloro-N2-(2-fluoro-5-methyl-4-(quinolin-3-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

trans-4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)- 2,5-dimethylphenyl)cyclohexanol

5-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2- methylphenyl)pyridin-2-ol

Trans-5-chloro-N2-(4-(4- (cyclopropylamino)cyclohexyl)-2,5-dimethylphenyl)-N4-(5-methyl-1H-pyrazol- 3-yl)pyrimidine-2,4-diamine

5-chloro-N2-(2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

Cis-5-chloro-N2-(4-(4- (cyclopropylamino)cyclohexyl)-2,5-dimethylphenyl)-N4-(5-methyl-1H-pyrazol- 3-yl)pyrimidine-2,4-diamine

5-chloro-N2-(2-fluoro-5-methyl-4-(thiophen-3-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

Cis-5-chloro-N2-(2-fluoro-5-methyl-4-(4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine

5-chloro-N2-(2-fluoro-4-(furan-3-yl)-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

Trans-5-chloro-N2-(2-fluoro-5-methyl-4-(4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine

5-chloro-N2-(2,5-dimethyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

Trans-5-chloro-N2-(2-fluoro-5-methyl-4-(4-morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine

5-chloro-N2-(2-fluoro-4-(furan-3-yl)-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

Cis-5-chloro-N2-(2-fluoro-5-methyl-4-(4-morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine

5-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)-N-methylpicolinamide

Cis-5-chloro-N2-(2-fluoro-5-methyl-4-(4-(4-methylpiperazin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine- 2,4-diamine

5-chloro-N2-(2,5-dimethyl-4-(2-methylpyridin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

Trans-5-chloro-N2-(2-fluoro-5-methyl-4-(4-(4-methylpiperazin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine- 2,4-diamine

5-chloro-N2-(2,5-dimethyl-4-(6-methylpyridin-3-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

(S)-1-((Cis)-4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5- fluoro-2-methylphenyl)cyclohexyl)pyrrolidin-3-ol

N2-(4-(1H-imidazol-2-yl)-2,5- dimethylphenyl)-5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

(S)-1-((Trans)-4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2- ylamino)-5-fluoro-2-methylphenyl)cyclohexyl)pyrrolidin-3-ol

5-chloro-N2-(2,5-dimethyl-4-(3-methylisoxazol-5-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

5-chloro-N2-(4-((cis)-4- (diethylamino)cyclohexyl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

5-chloro-N2-(2-fluoro-4-(1H-imidazol-2-yl)-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

5-chloro-N2-(4-((trans)-4- (diethylamino)cyclohexyl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

5-chloro-N2-(2,5-dimethyl-4-(oxazol-5-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

5-chloro-N2-(2-fluoro-5-methyl-4-((cis)-4-(piperazin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine

5-chloro-N2-(2-methoxy-5-methyl-4-(oxazol-5-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

5-chloro-N2-(2-fluoro-5-methyl-4-((trans)-4-(piperazin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine

5-chloro-N2-(2,5-dimethyl-4-(3-methyl-1H-pyrazol-5-yl)phenyl)-N4-(5-methyl- 1H-pyrazol-3-yl)pyrimidine-2,4-diamine

N2-(2,5-dimethyl-4-((cis)-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine- 2,4-diamine

5-chloro-N2-(2,5-dimethyl-4-(3-methylisoxazol-5-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

N2-(2,5-dimethyl-4-((trans)-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine- 2,4-diamine

5-chloro-N2-(2,5-dimethyl-4-(2-methylthiazol-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3- yl)pyrimidine-2,4-diamine

N2-(2-fluoro-5-methyl-4-((cis)-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine- 2,4-diamine

5-chloro-N2-(2,5-dimethyl-4-(1-methyl-1H-imidazol-2-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

N2-(2-fluoro-5-methyl-4-((trans)-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5- methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

N2-(4-(1H-imidazol-2-yl)-2,5- dimethylphenyl)-5-chloro-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

N2-(2-fluoro-5-methyl-4-((cis)-4- morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine

5-chloro-N2-(5-fluoro-2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine

N2-(2-fluoro-5-methyl-4-((trans)-4- morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine

1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)ethanone O-2-hydroxyethyl oxime

N2-(2,5-dimethyl-4-((cis)-4- morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine

1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)ethanone oxime

N2-(2,5-dimethyl-4-((trans)-4- morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine

4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-N,N,2,5- tetramethylbenzamide

(3S,4S)-1-((cis)-4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexyl)pyrrolidine-3,4- diol

4-(5-chloro-4-(5-methyl-1H-pyrazol-3- ylamino)pyrimidin-2-ylamino)-N-(2-(dimethylamino)ethyl)-2,5- dimethylbenzamide

(3S,4S)-1-((trans)-4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexyl)pyrrolidine-3,4- diol

(4-(5-chloro-4-(5-methyl-1H-pyrazol-3- ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)(morpholino)methanone

(3R,4R)-1-((trans)-4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexyl)pyrrolidine-3,4- diol

4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)cyclohexanone oxime

(3R,4R)-1-((cis)-4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5- (trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexyl)pyrrolidine-3,4- diol

1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)ethanone O-methyl oxime

Trans-4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)cyclohexanol

1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)ethanone O-2-(dimethylamino)ethyl oxime

Cis-4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2- methylphenyl)cyclohexanol

1-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5- dimethylphenyl)ethanone O-2-morpholinoethyl oxime

5-chloro-N2-(2,5-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine

Trans-5-chloro-N2-(2,5-dimethyl-4-(4-morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine

5-chloro-N2-(2,5-dimethyl-4-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine- 2,4-diamine

Cis-5-chloro-N2-(2,5-dimethyl-4-(4- morpholinocyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4- diamine


14. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 and a physiologically acceptablecarrier.
 15. A method for inhibiting IGF-1R in a cell, comprisingcontacting the cell with an effective amount of a compound of claim 1 ora pharmaceutical composition thereof.
 16. A method for treating anIGF-1R-mediated condition in a mammal suffering therefrom, comprisingadministering to the mammal a therapeutically effective amount of acompound of claim 1 or a pharmaceutical composition thereof, andoptionally in combination with a second therapeutic agent; wherein saidcondition is an autoimmune disease, a transplantation disease, aninfectious disease or a cell proliferative disorder.
 17. The method ofclaim 16, wherein said condition is a cell proliferative disorder. 18.The method of claim 17, wherein said cell proliferative disorder ismultiple myeloma, neuroblastoma, synovial, hepatocellular, Ewing'sSarcoma or a solid tumor selected from a osteosarcoma, melanoma, andtumor of breast, renal, prostate, colorectal, thyroid, ovarian,pancreatic, lung, uterine or gastrointestinal tumor.
 19. The method ofclaim 16, wherein said second therapeutic agent is a chemotherapeuticagent.
 20. (canceled)